CA2529152A1 - Process for the preparation of aromatic amines - Google Patents
Process for the preparation of aromatic amines Download PDFInfo
- Publication number
- CA2529152A1 CA2529152A1 CA002529152A CA2529152A CA2529152A1 CA 2529152 A1 CA2529152 A1 CA 2529152A1 CA 002529152 A CA002529152 A CA 002529152A CA 2529152 A CA2529152 A CA 2529152A CA 2529152 A1 CA2529152 A1 CA 2529152A1
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- CA
- Canada
- Prior art keywords
- formula
- compound
- optionally substituted
- process according
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- 238000000034 method Methods 0.000 title claims abstract description 58
- 230000008569 process Effects 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 150000004982 aromatic amines Chemical class 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 87
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract description 42
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 22
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 13
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims description 39
- 239000003446 ligand Substances 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 33
- 125000001424 substituent group Chemical group 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 229910052751 metal Inorganic materials 0.000 claims description 21
- 239000002184 metal Substances 0.000 claims description 21
- 239000000852 hydrogen donor Substances 0.000 claims description 20
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000000386 donor Substances 0.000 claims description 11
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 claims description 9
- 238000009901 transfer hydrogenation reaction Methods 0.000 claims description 9
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 230000007935 neutral effect Effects 0.000 claims description 7
- 239000010948 rhodium Substances 0.000 claims description 7
- GAWAYYRQGQZKCR-REOHCLBHSA-N (S)-2-chloropropanoic acid Chemical compound C[C@H](Cl)C(O)=O GAWAYYRQGQZKCR-REOHCLBHSA-N 0.000 claims description 6
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000005647 linker group Chemical group 0.000 claims description 5
- 230000000707 stereoselective effect Effects 0.000 claims description 5
- 239000011975 tartaric acid Substances 0.000 claims description 5
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical group CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 4
- 229910052703 rhodium Inorganic materials 0.000 claims description 4
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 4
- 125000000129 anionic group Chemical group 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- 101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 0.000 claims 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 125000003118 aryl group Chemical group 0.000 description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 125000000217 alkyl group Chemical group 0.000 description 20
- 125000004432 carbon atom Chemical group C* 0.000 description 19
- -1 group VIII metal Chemical class 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- 150000001412 amines Chemical class 0.000 description 11
- 125000004429 atom Chemical group 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 229910052717 sulfur Inorganic materials 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 230000035484 reaction time Effects 0.000 description 9
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- 238000007792 addition Methods 0.000 description 8
- 229940093499 ethyl acetate Drugs 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 235000019253 formic acid Nutrition 0.000 description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
- 125000005017 substituted alkenyl group Chemical group 0.000 description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 6
- 239000003638 chemical reducing agent Substances 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 150000004985 diamines Chemical class 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 150000003141 primary amines Chemical class 0.000 description 6
- QQLIGMASAVJVON-UHFFFAOYSA-N 1-naphthalen-1-ylethanone Chemical compound C1=CC=C2C(C(=O)C)=CC=CC2=C1 QQLIGMASAVJVON-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 150000002430 hydrocarbons Chemical class 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 125000004426 substituted alkynyl group Chemical group 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 150000001336 alkenes Chemical class 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 150000002739 metals Chemical class 0.000 description 4
- 150000003335 secondary amines Chemical class 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 150000001414 amino alcohols Chemical class 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229960002510 mandelic acid Drugs 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000003138 primary alcohols Chemical class 0.000 description 3
- 150000003333 secondary alcohols Chemical class 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- VYXHVRARDIDEHS-QGTKBVGQSA-N (1z,5z)-cycloocta-1,5-diene Chemical compound C\1C\C=C/CC\C=C/1 VYXHVRARDIDEHS-QGTKBVGQSA-N 0.000 description 2
- RUJHATQMIMUYKD-UHFFFAOYSA-N 2-naphthalen-1-ylethanamine Chemical compound C1=CC=C2C(CCN)=CC=CC2=C1 RUJHATQMIMUYKD-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 229910003827 NRaRb Inorganic materials 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000002877 alkyl aryl group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 229960000846 camphor Drugs 0.000 description 2
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- LQQCGEGRINLHDP-UHFFFAOYSA-N carboxyphosphoric acid Chemical compound OC(=O)OP(O)(O)=O LQQCGEGRINLHDP-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 150000001925 cycloalkenes Chemical class 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 230000005595 deprotonation Effects 0.000 description 2
- 238000010537 deprotonation reaction Methods 0.000 description 2
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052741 iridium Inorganic materials 0.000 description 2
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 125000002097 pentamethylcyclopentadienyl group Chemical group 0.000 description 2
- 230000000737 periodic effect Effects 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 229910052701 rubidium Inorganic materials 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 125000005415 substituted alkoxy group Chemical group 0.000 description 2
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 2
- 150000003457 sulfones Chemical class 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- PTMFUWGXPRYYMC-UHFFFAOYSA-N triethylazanium;formate Chemical compound OC=O.CCN(CC)CC PTMFUWGXPRYYMC-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- DLNKOYKMWOXYQA-VXNVDRBHSA-N (+)-norephedrine Chemical compound C[C@@H](N)[C@@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-VXNVDRBHSA-N 0.000 description 1
- DLNKOYKMWOXYQA-CBAPKCEASA-N (-)-norephedrine Chemical compound C[C@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-CBAPKCEASA-N 0.000 description 1
- LOPKSXMQWBYUOI-DTWKUNHWSA-N (1r,2s)-1-amino-2,3-dihydro-1h-inden-2-ol Chemical compound C1=CC=C2[C@@H](N)[C@@H](O)CC2=C1 LOPKSXMQWBYUOI-DTWKUNHWSA-N 0.000 description 1
- GEJJWYZZKKKSEV-UONOGXRCSA-N (1r,2s)-2-amino-1,2-diphenylethanol Chemical compound C1([C@@H](O)[C@@H](N)C=2C=CC=CC=2)=CC=CC=C1 GEJJWYZZKKKSEV-UONOGXRCSA-N 0.000 description 1
- ULSIYEODSMZIPX-MRVPVSSYSA-N (1s)-2-amino-1-phenylethanol Chemical compound NC[C@@H](O)C1=CC=CC=C1 ULSIYEODSMZIPX-MRVPVSSYSA-N 0.000 description 1
- LOPKSXMQWBYUOI-BDAKNGLRSA-N (1s,2r)-1-amino-2,3-dihydro-1h-inden-2-ol Chemical compound C1=CC=C2[C@H](N)[C@H](O)CC2=C1 LOPKSXMQWBYUOI-BDAKNGLRSA-N 0.000 description 1
- GEJJWYZZKKKSEV-KGLIPLIRSA-N (1s,2r)-2-amino-1,2-diphenylethanol Chemical compound C1([C@H](O)[C@H](N)C=2C=CC=CC=2)=CC=CC=C1 GEJJWYZZKKKSEV-KGLIPLIRSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- ZZJVTIQPKWYBTK-UHFFFAOYSA-N 1-(4,5-dihydro-1,3-oxazol-2-yl)-n-(4,5-dihydro-1,3-oxazol-2-ylmethyl)methanamine Chemical compound N=1CCOC=1CNCC1=NCCO1 ZZJVTIQPKWYBTK-UHFFFAOYSA-N 0.000 description 1
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- PQMCFTMVQORYJC-UHFFFAOYSA-N 2-aminocyclohexan-1-ol Chemical class NC1CCCCC1O PQMCFTMVQORYJC-UHFFFAOYSA-N 0.000 description 1
- JFFOUICIRBXFRC-UHFFFAOYSA-N 2-aminocyclopentan-1-ol Chemical class NC1CCCC1O JFFOUICIRBXFRC-UHFFFAOYSA-N 0.000 description 1
- NJBCRXCAPCODGX-UHFFFAOYSA-N 2-methyl-n-(2-methylpropyl)propan-1-amine Chemical compound CC(C)CNCC(C)C NJBCRXCAPCODGX-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical class [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- HVVNJUAVDAZWCB-RXMQYKEDSA-N D-prolinol Chemical compound OC[C@H]1CCCN1 HVVNJUAVDAZWCB-RXMQYKEDSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical class NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 1
- HVVNJUAVDAZWCB-YFKPBYRVSA-N [(2s)-pyrrolidin-2-yl]methanol Chemical compound OC[C@@H]1CCCN1 HVVNJUAVDAZWCB-YFKPBYRVSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000004951 benzene Polymers 0.000 description 1
- 150000001555 benzenes Polymers 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000004799 bromophenyl group Chemical group 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical group 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- SSJXIUAHEKJCMH-UHFFFAOYSA-N cyclohexane-1,2-diamine Chemical class NC1CCCCC1N SSJXIUAHEKJCMH-UHFFFAOYSA-N 0.000 description 1
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical class OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 150000002171 ethylene diamines Chemical class 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 229940013688 formic acid Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- CKAPSXZOOQJIBF-UHFFFAOYSA-N hexachlorobenzene Chemical compound ClC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl CKAPSXZOOQJIBF-UHFFFAOYSA-N 0.000 description 1
- YUWFEBAXEOLKSG-UHFFFAOYSA-N hexamethylbenzene Chemical compound CC1=C(C)C(C)=C(C)C(C)=C1C YUWFEBAXEOLKSG-UHFFFAOYSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- ITNLZZDQOMWQDT-FIQIYMRGSA-N n-[(1s)-2-amino-1,2-diphenylethyl]-1-[(1s,4s)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonamide Chemical compound NC([C@@H](NS(=O)(=O)C[C@@]12CC[C@@](CC2=O)(C1(C)C)[H])C=1C=CC=CC=1)C1=CC=CC=C1 ITNLZZDQOMWQDT-FIQIYMRGSA-N 0.000 description 1
- PXSXRABJBXYMFT-UHFFFAOYSA-N n-hexylhexan-1-amine Chemical compound CCCCCCNCCCCCC PXSXRABJBXYMFT-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 238000011445 neoadjuvant hormone therapy Methods 0.000 description 1
- SJYNFBVQFBRSIB-UHFFFAOYSA-N norbornadiene Chemical compound C1=CC2C=CC1C2 SJYNFBVQFBRSIB-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229920000233 poly(alkylene oxides) Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- YAYGSLOSTXKUBW-UHFFFAOYSA-N ruthenium(2+) Chemical compound [Ru+2] YAYGSLOSTXKUBW-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000011916 stereoselective reduction Methods 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
- C07C309/66—Methanesulfonates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
- C07C209/14—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of hydroxy groups or of etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
- C07C209/14—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of hydroxy groups or of etherified or esterified hydroxy groups
- C07C209/16—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of hydroxy groups or of etherified or esterified hydroxy groups with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/86—Separation
- C07C209/88—Separation of optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
There is provided a process for the preparation of aromatic amines of Formula (1): where Rx is optionally substituted aryl and Ry is optionally substituted hydrocarbyl, which comprises: (a) reducing a compound of Formula (2): to give a compound of Formula (3): then, (b) reacting a compound of Formula (3) with a leaving group donor, to give a compound of Formula (4); and, (c) reacting a compound of Formula (4) with ammonia to give the compound of Formula (1).
Description
PROCESS FOR THE PREPARATION OF AROMATIC AMINES
This invention relates to processes for the preparation of chiral aromatic amines and to novel substituted chiral aromatic amines.
Enantiomers of aromatic amines, such as 1-naphthylethylamine are valuable building blocks in the preparation of pharmaceutical and agrochemical active agents.
They are also used as resolving agents for crystallisation/resolution of acidic species and as a chiral auxiliary.
According to a first aspect of the present invention there is provided a process for the preparation of a compound of Formula (1 ):
N HZ
RX~Rv Formula (1 ) wherein:
RX is optionally substituted aryl; and Ry is optionally substituted hydrocarbyl:
which comprises the steps:
(a) reducing a compound of Formula (2):
Rx~Rv Formula (2) to a compound of Formula (3):
OH
Rx~ Rv Formula (3) wherein RX and Ry are as defined for Formula (1 ):
(b) reacting a compound of Formula (3) with a leaving group donor, to give a compound of Formula (4);
OL
~,X~Rv Formula (4) wherein:
CONFIRMATION COPY
This invention relates to processes for the preparation of chiral aromatic amines and to novel substituted chiral aromatic amines.
Enantiomers of aromatic amines, such as 1-naphthylethylamine are valuable building blocks in the preparation of pharmaceutical and agrochemical active agents.
They are also used as resolving agents for crystallisation/resolution of acidic species and as a chiral auxiliary.
According to a first aspect of the present invention there is provided a process for the preparation of a compound of Formula (1 ):
N HZ
RX~Rv Formula (1 ) wherein:
RX is optionally substituted aryl; and Ry is optionally substituted hydrocarbyl:
which comprises the steps:
(a) reducing a compound of Formula (2):
Rx~Rv Formula (2) to a compound of Formula (3):
OH
Rx~ Rv Formula (3) wherein RX and Ry are as defined for Formula (1 ):
(b) reacting a compound of Formula (3) with a leaving group donor, to give a compound of Formula (4);
OL
~,X~Rv Formula (4) wherein:
CONFIRMATION COPY
Rx and RY are as defined for Formula (1 ); and OL is a leaving group:
(c) reacting a compound of Formula (4) with ammonia to give a compound of Formula (1).
Preferably Ry is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl or any combination thereof.
When RY comprises optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl it may be a linear, branched or cyclic molecule.
It is particularly preferred that Ry is optionally substituted alkyl, especially optionally substituted C~~alkyl, particularly C~.~alkyl and more particularly methyl.
RX is preferably optionally substituted phenyl or optionally substituted napthyl more preferably RX is optionally substituted napthyl.
In many embodiments R" and R'' are different.
Thus, there is preferably provided a process for the preparation of a compound of Formula (5):
R~ NNa \ \
R' )n / /
Formula (5) wherein:
R' is a substituent;
R~ is optionally substituted hydrocarbyl; and n is 0 to 4:
which comprises the steps:
(a) reducing a compound of Formula (6):
RZ O
\ \
Rj)n / /
Formula (6) to a compound of Formula (7):
(c) reacting a compound of Formula (4) with ammonia to give a compound of Formula (1).
Preferably Ry is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl or any combination thereof.
When RY comprises optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl it may be a linear, branched or cyclic molecule.
It is particularly preferred that Ry is optionally substituted alkyl, especially optionally substituted C~~alkyl, particularly C~.~alkyl and more particularly methyl.
RX is preferably optionally substituted phenyl or optionally substituted napthyl more preferably RX is optionally substituted napthyl.
In many embodiments R" and R'' are different.
Thus, there is preferably provided a process for the preparation of a compound of Formula (5):
R~ NNa \ \
R' )n / /
Formula (5) wherein:
R' is a substituent;
R~ is optionally substituted hydrocarbyl; and n is 0 to 4:
which comprises the steps:
(a) reducing a compound of Formula (6):
RZ O
\ \
Rj)n / /
Formula (6) to a compound of Formula (7):
R~ OH
\ \
R~ )n Formula (7) wherein R', RZ and n are as defined for Formula (5):
(b) reacting a compound of Formula (7) with a leaving group donor, to give a compound of Formula (8);
R~ OL
\ \
R1)n Formula (8) wherein:
R', R~ and n are as defined for Formula (5);
OL is a leaving group:
(c) reacting a compound of Formula (8) with ammonia to give a compound of Formula (5).
Preferably Ra is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl or any combination thereof.
When R~ comprises optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl it may be a linear, branched or cyclic molecule.
It is particularly preferred that R~ is optionally substituted alkyl, especially optionally substituted C~~alkyl, particularly C~~alkyl and more particularly methyl.
In the compounds of Formulae (1 ) to (8) the optional substituents on R'' and R~ are preferably independently selected from: optionally substituted alkoxy (preferably C~_4-alkoxy), optionally substituted aryl (preferably phenyl), optionally substituted aryloxy (preferably phenoxy), optionally substituted heterocyclyl, polyalkyiene oxide (preferably polyethylene oxide or polypropylene oxide), carboxy, phosphate, sulfo, nitre, cyano, halo, ureido, -SOzF, hydroxy, ester, -NRaRb, -CORa, -CONRaRb, -NHCORa, carboxyester, sulfone, and -S02NRaRb wherein Ra and Rb are each independently H or optionally substituted alkyl (especially C~_4-alkyl). Optional substituents for any of the substituents described for Ry and R2 may be selected from the same list of substituents.
In the compounds of Formulae (1 ) to (8) the optional substituents on Rx and substituents R' are preferably independently selected from: optionally substituted alkyl (preferably C~~-alkyl), optionally substituted alkenyl (preferably C~~.-alkenyl), optionally substituted alkynyl (preferably C~~-alkynyl), optionally substituted alkoxy (preferably C,.~-alkoxy), optionally substituted aryl (preferably phenyl), optionally substituted aryloxy (preferably phenoxy), optionally substituted heterocyclyl, polyalkylene oxide (preferably polyethylene oxide or polypropylene oxide), carboxy, phosphate, sulfo, nitre, cyano, halo, ureido, -S02F, hydroxy, ester, -NRaRb, -CORa, -CONRaRb, -NHCORa, carboxyester, sulfone, and -SOzNRaRb wherein Ra and Rb are each independently H or optionally substituted alkyl (especially C~~-alkyl). Optional substituents for any of the above substituents may be selected from the list of substituents preferred for R'' and R2.
Preferably n is 0.
The reduction of the keto group in a compound of Formula (2) or Formula (5) in step (a) may be carried out using any suitable method known in the art. These methods are summarised in Larock R.C., Comprehensive Organic Transformations, VCH, pages 527 to 548 which is included herein by reference and include reduction with:
LiAIH4, diisobutyl aluminium hydride (D1BAL), NaBH4 or BH3; reduction by a biological system, such as an enzyme or a microbial cell or cell preparation; or reduction using a Nobel metal or Raney catalyst such as Pt in the presence of hydrogen.
Step (a) is preferably carried out in the presence of a catalyst.
Catalysts include transfer hydrogenation catalysts such as: (a) the chiral Ruthenium (II) catalysts developed for ketone reduction which are disclosed in Chem.
Rev., 1998, 98, 2607 see Table 2; (b) the Zhang tridentate bis(oxazolinylmethyl)amine catalysts and related catalysts as disclosed in J. Am. Chem. Sec., 1998, 120, 3817, Tet.
Let., 1997, 38(37), 6565 and in W099/24410 (particularly the bis(phenyloxazolin-2 yl)amine and related catalysts discussed therein); and (c) the transition metal, particularly group VIII metal, complexes with chiral ligands of formula:
R' ~AR~ R' R,~._.p ~P~R~~
. R"' . R"' wherein AR is any aromatic or ring structure and R', R" and R"' are each independently selected from aryl, alkyl, aralkyl, ring-substituted aralkyl, substituted aryl and combinations thereof as disclosed in US 5,767,276, the catalysts of (a), (b) and (c) being incorporated herein by reference.
However, in a preferred embodiment step (a) is a transfer hydrogenation carried out using a hydrogen donor and a catalyst as described in International Patent Applications WO 98/42643, WO 00/18708 and WO 01112574 which references are incorporated herein, in their entirety, by reference.
The preferred transfer hydrogenation catalysts for use in the process of the present invention are of general Formula (A):
~E~
A~ ~B
s ~3 tCY
Formula (A) 5 wherein:
R3 represents a neutral optionally substituted hydrocarbyl, a neutral optionally substituted perhalogenated hydrocarbyl, or an optionally substituted cyciopentadienyl ligand;
A represents -NR4-, -NR5-, -NHR4, -NR4R5 or -NR5R6 where R4 is H, C(O)RE, S02R6, C(O)NR6R'°, C(S)NR6R'°, C(=NR'°)SR" or C(=NR'°)OR", R5 and R6 each independently represents an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, and R'°
and R" are each independently hydrogen or a group as defined for R6;
B represents -O-, -OH, OR', -S-, -SH, SR', -NR'-, -NR$-, -NHRB, -NR'R8, -NR'R9, -PR'- or -PR7R9 where R8 is H, C(O)R9, S02R9, C(O)NR9R'z, C(S)NR9R'2, C(=NR'~)SR'3 or C(=NR'2)OR'3, R'and Rg each independently represents an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, and R'2 and R'3 are each independently hydrogen or a group as defined for R9;
E represents a linking group;
M represents a metal capable of catalysing transfer hydrogenation; and Y represents an anionic group, a basic ligand or a vacant site;
provided that when Y is not a vacant site that at least one of A or B carries a hydrogen atom.
The catalytic species is believed to be substantially as represented in the above formula. It may be introduced on a solid support.
Optionally substituted hydrocarbyl groups represented by R5-' or R9'" include alkyl, alkenyl, aikynyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl, for example benzyl groups.
Alkyl groups which may be represented by R5-7 or R9-" include linear and branched alkyl groups comprising 1 to 20 carbon atoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5 carbon atoms. In certain embodiments, the alkyl group may be cyclic, commonly comprising from 3 to 10 carbon atoms in the largest ring and optionally featuring one or more bridging rings. Examples of alkyl groups which may be represented by R5'' or R99-" include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl , and cyclohexyl groups.
Alkenyl groups which may be represented by one or more of R5-' or 89-11 include C2_2°, and preferably CZ_s alkenyl groups. One or more carbon - carbon double bonds may be present. The alkenyl group may carry one or more substituents, particularly phenyl substituents.
Alkynyl groups which may be represented by one or more of R5-' or R9-" include C2_2o, and preferably C2_,o alkynyl groups. One or more carbon - carbon triple bonds may be present. The alkynyl group may carry one or more substituents, particularly phenyl substituents. Examples of alkynyl groups include ethynyl, propyl and phenylethynyl groups.
Aryl groups which may be represented by one or more of R5-' or R9-" may contain 1 ring or 2 or more fused or bridged rings which may include cycloalkyl, aryl or heterocyclic rings. Examples of aryl groups which may be represented by R5-' or R9-"
include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl and ferrocenyl groups.
Perhalogenated hydrocarbyl groups which may be represented by one or more of R5-' or R9-" independently include perhalogenated alkyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl groups. Examples of perhalogenated alkyl groups which may be represented by R5-'' or R9-" include-CF3 and -C2F5.
Heterocyclic groups which may be represented by one or more of R5-' or R9-"
independently include aromatic, saturated and partially unsaturated ring systems and may comprise 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. The heterocyclic group will contain at least one heterocyclic ring, the largest of which will commonly comprise from 3 to 7 ring atoms in which at least one atom is carbon and at least one atom is any of N, O, S or P. Examples of heterocyclic groups which may be represented by R5-' or R9-" include pyridyl, pyrimidyl, pyrrolyl, thiophenyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazolyl and triazolyl groups.
When any of R5-' or R9-" is a substituted hydrocarbyl or heterocyclic group, the substituent(s) should be such so as not to adversely affect the rate or stereoselectivity of the reaction. Optional substituents include halogen, cyano, nitro, hydroxy, amino, imino, thiol, acyl, hydrocarbyl, perhalogenated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carboxy, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R5'' or R9-"
above. One or more substituents may be present. R5-' or R9-" may each contain one or more chiral centres.
The neutral optionally substituted hydrocarbyl or perhalogenated hydrocarbyl ligand which may be represented by R3 includes optionally substituted aryl and alkenyl ligands.
Optionally substituted aryl ligands which may be represented by R3 may contain ring or 2 or more fused rings which include cycloalkyl, aryl or heterocyclic rings.
Preferably, the ligand comprises a 6 membered aromatic ring. The ring or rings of the aryl ligand are often substituted with hydrocarbyl groups. The substitution pattern and the number of substituents will vary and may be influenced by the number of rings present, but often from 1 to 6 hydrocarbyl substituent groups are present, preferably 2, 3 or 6 hydrocarbyl groups and more preferably 6 hydrocarbyl groups. Preferred hydrocarbyl substituents include methyl, ethyl, iso-propyl, menthyl, neomenthyl and phenyl.
Particularly when the aryl ligand is a single ring, the ligand is preferably benzene or a substituted benzene. When the ligand is a perhalogenated hydrocarbyl, preferably it is a polyhalogenated benzene such as hexachlorobenzene or hexafluorobenzne. When the hydrocarbyl substitutents contain enantiomeric andlor diastereomeric centres, it is preferred that the enantiomerically andlor diastereomerically purified forms of these are used. Benzene, p-cymyl, mesitylene and hexamethylbenzene are especially preferred ligands.
Optionally substituted alkenyl ligands which may be represented by R3 include C~-3o, and preferably C6_~2, alkenes or cycloalkenes with preferably two or more carbon-carbon double bonds, preferably only two carbon-carbon double bonds. The carbon-carbon double bonds may optionally be conjugated to other unsaturated systems which may be present, but are preferably conjugated to each other. The alkenes or cycloalkenes may be substituted preferably with hydrocarbyl substituents. When the alkene has only one double bond, the optionally substituted alkenyl ligand may comprise two separate alkenes. Preferred hydrocarbyl substituents include methyl, ethyl, iso-propyl and phenyl. Examples of optionally substituted alkenyl ligands include cyclo-octa-1,5 diene and 2,5-norbornadiene. Cyclo-octa-1,5-diene is especially preferred.
Optionally substituted cyclopentadienyl groups which may be represented by R3 include cyclopentadienyl groups capable of eta-5 bonding. The cyclopentadienyl group is often substituted with from 1 to 5 hydrocarbyl groups, preferably with 3 to 5 hydrocarbyl groups and more preferably with 5 hydrocarbyl groups. Preferred hydrocarbyl substituents include methyl, ethyl and phenyl. When the hydrocarbyl substitutents contain ehantiomeric and/or diastereomeric centres, it is preferred that the enantiomerically and/or diastereomerically purified forms of these are used. Examples of optionally substituted cyclopentadienyl groups include cyclopentadienyl, pentamethyl-cyclopentadienyl, pentaphenylcyclopentadienyl, tetraphenylcyclopentadienyl, ethyltetramethylpentadienyl, menthyltetraphenylcyclopentadienyl, neomenthyl-tetraphenylcyclopentadienyl, menthylcyclopentadienyl, neomenthylcyclopentadienyl, tetrahydroindenyl, menthyltetrahydroindenyl and neomenthyltetrahydroindenyl groups.
Pentamethylcyclopentadienyl is especially preferred.
When either A or B is an amide group represented by -NR4-, -NHR4, NR4R5, -NR$-, -NHRs or NR'R8 wherein R5 and R' are as hereinbefore defined, and where R4 or R$ is an acyl group represented by -C(O)RE or -C(O)R9, R6 and R9 independently are often linear or branched C~_~alkyl, C~_s-cycloalkyl or aryl, for example phenyl. Examples of acyl groups which may be represented by R4 or R9 include benzoyl, acetyl and halogenoacetyl, especially trifluoroacetyl groups.
\ \
R~ )n Formula (7) wherein R', RZ and n are as defined for Formula (5):
(b) reacting a compound of Formula (7) with a leaving group donor, to give a compound of Formula (8);
R~ OL
\ \
R1)n Formula (8) wherein:
R', R~ and n are as defined for Formula (5);
OL is a leaving group:
(c) reacting a compound of Formula (8) with ammonia to give a compound of Formula (5).
Preferably Ra is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl or any combination thereof.
When R~ comprises optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl it may be a linear, branched or cyclic molecule.
It is particularly preferred that R~ is optionally substituted alkyl, especially optionally substituted C~~alkyl, particularly C~~alkyl and more particularly methyl.
In the compounds of Formulae (1 ) to (8) the optional substituents on R'' and R~ are preferably independently selected from: optionally substituted alkoxy (preferably C~_4-alkoxy), optionally substituted aryl (preferably phenyl), optionally substituted aryloxy (preferably phenoxy), optionally substituted heterocyclyl, polyalkyiene oxide (preferably polyethylene oxide or polypropylene oxide), carboxy, phosphate, sulfo, nitre, cyano, halo, ureido, -SOzF, hydroxy, ester, -NRaRb, -CORa, -CONRaRb, -NHCORa, carboxyester, sulfone, and -S02NRaRb wherein Ra and Rb are each independently H or optionally substituted alkyl (especially C~_4-alkyl). Optional substituents for any of the substituents described for Ry and R2 may be selected from the same list of substituents.
In the compounds of Formulae (1 ) to (8) the optional substituents on Rx and substituents R' are preferably independently selected from: optionally substituted alkyl (preferably C~~-alkyl), optionally substituted alkenyl (preferably C~~.-alkenyl), optionally substituted alkynyl (preferably C~~-alkynyl), optionally substituted alkoxy (preferably C,.~-alkoxy), optionally substituted aryl (preferably phenyl), optionally substituted aryloxy (preferably phenoxy), optionally substituted heterocyclyl, polyalkylene oxide (preferably polyethylene oxide or polypropylene oxide), carboxy, phosphate, sulfo, nitre, cyano, halo, ureido, -S02F, hydroxy, ester, -NRaRb, -CORa, -CONRaRb, -NHCORa, carboxyester, sulfone, and -SOzNRaRb wherein Ra and Rb are each independently H or optionally substituted alkyl (especially C~~-alkyl). Optional substituents for any of the above substituents may be selected from the list of substituents preferred for R'' and R2.
Preferably n is 0.
The reduction of the keto group in a compound of Formula (2) or Formula (5) in step (a) may be carried out using any suitable method known in the art. These methods are summarised in Larock R.C., Comprehensive Organic Transformations, VCH, pages 527 to 548 which is included herein by reference and include reduction with:
LiAIH4, diisobutyl aluminium hydride (D1BAL), NaBH4 or BH3; reduction by a biological system, such as an enzyme or a microbial cell or cell preparation; or reduction using a Nobel metal or Raney catalyst such as Pt in the presence of hydrogen.
Step (a) is preferably carried out in the presence of a catalyst.
Catalysts include transfer hydrogenation catalysts such as: (a) the chiral Ruthenium (II) catalysts developed for ketone reduction which are disclosed in Chem.
Rev., 1998, 98, 2607 see Table 2; (b) the Zhang tridentate bis(oxazolinylmethyl)amine catalysts and related catalysts as disclosed in J. Am. Chem. Sec., 1998, 120, 3817, Tet.
Let., 1997, 38(37), 6565 and in W099/24410 (particularly the bis(phenyloxazolin-2 yl)amine and related catalysts discussed therein); and (c) the transition metal, particularly group VIII metal, complexes with chiral ligands of formula:
R' ~AR~ R' R,~._.p ~P~R~~
. R"' . R"' wherein AR is any aromatic or ring structure and R', R" and R"' are each independently selected from aryl, alkyl, aralkyl, ring-substituted aralkyl, substituted aryl and combinations thereof as disclosed in US 5,767,276, the catalysts of (a), (b) and (c) being incorporated herein by reference.
However, in a preferred embodiment step (a) is a transfer hydrogenation carried out using a hydrogen donor and a catalyst as described in International Patent Applications WO 98/42643, WO 00/18708 and WO 01112574 which references are incorporated herein, in their entirety, by reference.
The preferred transfer hydrogenation catalysts for use in the process of the present invention are of general Formula (A):
~E~
A~ ~B
s ~3 tCY
Formula (A) 5 wherein:
R3 represents a neutral optionally substituted hydrocarbyl, a neutral optionally substituted perhalogenated hydrocarbyl, or an optionally substituted cyciopentadienyl ligand;
A represents -NR4-, -NR5-, -NHR4, -NR4R5 or -NR5R6 where R4 is H, C(O)RE, S02R6, C(O)NR6R'°, C(S)NR6R'°, C(=NR'°)SR" or C(=NR'°)OR", R5 and R6 each independently represents an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, and R'°
and R" are each independently hydrogen or a group as defined for R6;
B represents -O-, -OH, OR', -S-, -SH, SR', -NR'-, -NR$-, -NHRB, -NR'R8, -NR'R9, -PR'- or -PR7R9 where R8 is H, C(O)R9, S02R9, C(O)NR9R'z, C(S)NR9R'2, C(=NR'~)SR'3 or C(=NR'2)OR'3, R'and Rg each independently represents an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, and R'2 and R'3 are each independently hydrogen or a group as defined for R9;
E represents a linking group;
M represents a metal capable of catalysing transfer hydrogenation; and Y represents an anionic group, a basic ligand or a vacant site;
provided that when Y is not a vacant site that at least one of A or B carries a hydrogen atom.
The catalytic species is believed to be substantially as represented in the above formula. It may be introduced on a solid support.
Optionally substituted hydrocarbyl groups represented by R5-' or R9'" include alkyl, alkenyl, aikynyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl, for example benzyl groups.
Alkyl groups which may be represented by R5-7 or R9-" include linear and branched alkyl groups comprising 1 to 20 carbon atoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5 carbon atoms. In certain embodiments, the alkyl group may be cyclic, commonly comprising from 3 to 10 carbon atoms in the largest ring and optionally featuring one or more bridging rings. Examples of alkyl groups which may be represented by R5'' or R99-" include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl , and cyclohexyl groups.
Alkenyl groups which may be represented by one or more of R5-' or 89-11 include C2_2°, and preferably CZ_s alkenyl groups. One or more carbon - carbon double bonds may be present. The alkenyl group may carry one or more substituents, particularly phenyl substituents.
Alkynyl groups which may be represented by one or more of R5-' or R9-" include C2_2o, and preferably C2_,o alkynyl groups. One or more carbon - carbon triple bonds may be present. The alkynyl group may carry one or more substituents, particularly phenyl substituents. Examples of alkynyl groups include ethynyl, propyl and phenylethynyl groups.
Aryl groups which may be represented by one or more of R5-' or R9-" may contain 1 ring or 2 or more fused or bridged rings which may include cycloalkyl, aryl or heterocyclic rings. Examples of aryl groups which may be represented by R5-' or R9-"
include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl and ferrocenyl groups.
Perhalogenated hydrocarbyl groups which may be represented by one or more of R5-' or R9-" independently include perhalogenated alkyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl groups. Examples of perhalogenated alkyl groups which may be represented by R5-'' or R9-" include-CF3 and -C2F5.
Heterocyclic groups which may be represented by one or more of R5-' or R9-"
independently include aromatic, saturated and partially unsaturated ring systems and may comprise 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. The heterocyclic group will contain at least one heterocyclic ring, the largest of which will commonly comprise from 3 to 7 ring atoms in which at least one atom is carbon and at least one atom is any of N, O, S or P. Examples of heterocyclic groups which may be represented by R5-' or R9-" include pyridyl, pyrimidyl, pyrrolyl, thiophenyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazolyl and triazolyl groups.
When any of R5-' or R9-" is a substituted hydrocarbyl or heterocyclic group, the substituent(s) should be such so as not to adversely affect the rate or stereoselectivity of the reaction. Optional substituents include halogen, cyano, nitro, hydroxy, amino, imino, thiol, acyl, hydrocarbyl, perhalogenated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carboxy, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R5'' or R9-"
above. One or more substituents may be present. R5-' or R9-" may each contain one or more chiral centres.
The neutral optionally substituted hydrocarbyl or perhalogenated hydrocarbyl ligand which may be represented by R3 includes optionally substituted aryl and alkenyl ligands.
Optionally substituted aryl ligands which may be represented by R3 may contain ring or 2 or more fused rings which include cycloalkyl, aryl or heterocyclic rings.
Preferably, the ligand comprises a 6 membered aromatic ring. The ring or rings of the aryl ligand are often substituted with hydrocarbyl groups. The substitution pattern and the number of substituents will vary and may be influenced by the number of rings present, but often from 1 to 6 hydrocarbyl substituent groups are present, preferably 2, 3 or 6 hydrocarbyl groups and more preferably 6 hydrocarbyl groups. Preferred hydrocarbyl substituents include methyl, ethyl, iso-propyl, menthyl, neomenthyl and phenyl.
Particularly when the aryl ligand is a single ring, the ligand is preferably benzene or a substituted benzene. When the ligand is a perhalogenated hydrocarbyl, preferably it is a polyhalogenated benzene such as hexachlorobenzene or hexafluorobenzne. When the hydrocarbyl substitutents contain enantiomeric andlor diastereomeric centres, it is preferred that the enantiomerically andlor diastereomerically purified forms of these are used. Benzene, p-cymyl, mesitylene and hexamethylbenzene are especially preferred ligands.
Optionally substituted alkenyl ligands which may be represented by R3 include C~-3o, and preferably C6_~2, alkenes or cycloalkenes with preferably two or more carbon-carbon double bonds, preferably only two carbon-carbon double bonds. The carbon-carbon double bonds may optionally be conjugated to other unsaturated systems which may be present, but are preferably conjugated to each other. The alkenes or cycloalkenes may be substituted preferably with hydrocarbyl substituents. When the alkene has only one double bond, the optionally substituted alkenyl ligand may comprise two separate alkenes. Preferred hydrocarbyl substituents include methyl, ethyl, iso-propyl and phenyl. Examples of optionally substituted alkenyl ligands include cyclo-octa-1,5 diene and 2,5-norbornadiene. Cyclo-octa-1,5-diene is especially preferred.
Optionally substituted cyclopentadienyl groups which may be represented by R3 include cyclopentadienyl groups capable of eta-5 bonding. The cyclopentadienyl group is often substituted with from 1 to 5 hydrocarbyl groups, preferably with 3 to 5 hydrocarbyl groups and more preferably with 5 hydrocarbyl groups. Preferred hydrocarbyl substituents include methyl, ethyl and phenyl. When the hydrocarbyl substitutents contain ehantiomeric and/or diastereomeric centres, it is preferred that the enantiomerically and/or diastereomerically purified forms of these are used. Examples of optionally substituted cyclopentadienyl groups include cyclopentadienyl, pentamethyl-cyclopentadienyl, pentaphenylcyclopentadienyl, tetraphenylcyclopentadienyl, ethyltetramethylpentadienyl, menthyltetraphenylcyclopentadienyl, neomenthyl-tetraphenylcyclopentadienyl, menthylcyclopentadienyl, neomenthylcyclopentadienyl, tetrahydroindenyl, menthyltetrahydroindenyl and neomenthyltetrahydroindenyl groups.
Pentamethylcyclopentadienyl is especially preferred.
When either A or B is an amide group represented by -NR4-, -NHR4, NR4R5, -NR$-, -NHRs or NR'R8 wherein R5 and R' are as hereinbefore defined, and where R4 or R$ is an acyl group represented by -C(O)RE or -C(O)R9, R6 and R9 independently are often linear or branched C~_~alkyl, C~_s-cycloalkyl or aryl, for example phenyl. Examples of acyl groups which may be represented by R4 or R9 include benzoyl, acetyl and halogenoacetyl, especially trifluoroacetyl groups.
When either A or B is present as a sulphonamide group represented by -NR4-, -NHR4, NR4R5, -NR$-, -NHR$ or NR'R$ wherein R5 and R' are as hereinbefore defined, and where R4 or Ra is a sulphonyl group represented by -S(O)2R6 or -S(O)~R9, R6 and R9 independently are often linear or branched C,_$alkyl, C~_$cycloalkyl or aryl, for example phenyl. Preferred sulphonyl groups include methanesufphonyl, trifluoromethanesulphonyf and especially p-toluenesulphonyl groups and naphthylsulphonyl groups.
When either of A or B is present as a group represented by -NR4-, -NHR4, NR4R5, -NR8-, -NHRB or NR'R$ wherein R5 and R are as hereinbefore defined, and where R$ or R$
is a group represented by C(O)NR6R'°, C(S)NRsR'o, C(=NR'°)SR", C(=NR'°)OR", C(O)NR9R'~, C(S)NR9R'2, C(=NR'2)SR'3 or C(=NR'z)OR'3, R6 and R9 independently are often linear or branched C~_$alkyl, such as methyl, ethyl, isopropyl, C~_$cycloalkyl or aryl, for example phenyl, groups and R'o-'3 are often each independently hydrogen or linear or branched C~_aalkyl, such as methyl, ethyl, isopropyl, C,_acycloalkyl or aryl, for example phenyl, groups.
When B is present as a group represented by -OR', -SR','-PR'- or -PR'R9, R' and R9 independently are often linear or branched C,_8alkyl, such as methyl, ethyl, isopropyl, C~_$cycloalkyl or aryl, for example phenyl.
It will be recognised that the precise nature of A and B will be determined by whether A and/or B are formally bonded to the metal or are coordinated to the metal via a lone pair of electrons.
The groups A and B are connected by a linking group E. The linking group E
achieves a suitable conformation of A and B so as to allow both A and B to bond or coordinate to the metal, M. A and B are commonly linked through 2, 3 or 4 atoms. The atoms in E linking A and B may carry one or more substituents. The atoms in E, especially the atoms alpha to A or B, may be linked to A and B, in such a way as to form a heterocyclic ring, preferably a saturated ring, and particularly a 5, 6 or 7-membered ring.
Such a ring may be fused to one or more other rings. Often the atoms linking A
and B will be carbon atoms. Preferably, one or more of the carbon atoms linking A and B
will carry substituents in addition to A or B. Substituent groups include those which may substitute R5-' or R9-" as defined above. Advantageously, any such substituent groups are selected to be groups which do not coordinate with the metal, M. Preferred substituents include halogen, cyano, nitro, sulphonyl, hydrocarbyl, perhalogenated hydrocarbyl and heterocyclyl groups as defined above. Most preferred substituents are C~_6 alkyl groups, and phenyl groups. Most preferably, A and B are linked by two carbon atoms, and especially an optionally substituted ethyl moiety. When A and B are linked by two carbon atoms, the two carbon atoms linking A and B may comprise part of an aromatic or aliphatic cyclic group, particularly a 5, 6 or 7-membered ring. Such a ring may be fused to one or more other such rings. Particularly preferred are embodiments in which E
represents a 2 carbon atom separation and one or both of the carbon atoms carries an optionally substituted aryl group as defined above or E represents a 2 carbon atom separation which comprises a cyclopentane or cyclohexane ring, optionally fiused to a phenyl ring.
E preferably comprises part of a compound having at least one stereospecifiic centre. Where any or all of the 2, 3 or 4 atoms linking A and B are substituted so as to define at least one stereospecific centre on one or more of these atoms, it is preferred that at least one of the stereospecific centres be located at the atom adjacent to either group A
or B. When at least one such stereospecific centre is present, it is advantageously present in an enantiomerically purified state.
When B represents -O- or -OH, and the adjacent atom in E is carbon, it is preferred that B does not form part of a carboxylic group.
Compounds which may be represented by A-E-B, or from which A-E-B may be derived by deprotonation, are often aminoalcohols, including 4-aminoalkan-1-ols, 1-aminoalkan-4-ols, 3-aminoalkan-1-ols, 1-aminoalkan-3-ols, and especially 2-aminoalkan-1-ols, 1-aminoalkan-2-ols, 3-aminoalkan-2-ols and 2-aminoalkan-3-ols, and particularly 2-aminoethanols or 3-aminopropanols, or are diamines, including 1,4-diaminoalkanes, 1,3-diaminoalkanes, especially 1,2- or 2,3-diariiinoalkanes and particularly ethylenediamines. Further aminoalcohols that may be represented by A-E-B
are 2-aminocyclopentanols and 2-aminocyclohexanols, preferably fused to a phenyl ring.
Further diamines that may be represented by A-E-B are 1,2-diaminocycloperitanes and 1,2-diaminocyclohexanes, preferably fused to a phenyl ring. The amino groups may advantageously be N-tosylated. When a diamine is represented by A-E-B, preferably at least one amino group is N-tosylated. The aminoalcohols or diamines are advantageously substituted, especially on the linking group, E, by at feast one alkyl group, such as a C~_4-alkyl, and particularly a methyl, group or at least one aryl group, particularly a phenyl group.
Specific examples of compounds which can be represented by A-E-B and the protonated equivalents from which they may be derived are:
H3 ' .Ph Ph' -Ph Ph~ h Ph_ Ph HZN//~/~\OH HzN//~/\\NH-tosyl HzN/~/\NHz HzN/~~/NH-SOZ naphthyl ~~ N H-tosyl Ph CH3 Ph Ph PhCH CsHaOMe u /~ z~C6H40Me NHz HzN~ H HO NHz H ~ HZ HzN/ \NHz N
H OH
H N tosyl-HN
HZN HO z HzN
NHz OH NHz HO NHz Preferably, the enantiomerically and/or diastereomerically purified forms of these are used. Examples include (1 S,2R)-(+)-norephedrine, (1 R,2S)-(+)-cis-1-amino-2-indanol, (1 S,2R)-2-amino-1,2-diphenylethanol, (1 S,2R)-(-)-cis-1-amino-2-indanol, (1 R,2S)-(-)-norephedrine, (S)-(+)-2-amino-1-phenylethanol, (1R,2S)-2-amino-1,2-diphenylethanol, N-5 tosyl-(1R,2R)-1,2-diphenylethyfenediamine, N-tosyf-(1S,2S)-1,2-diphenylethylenediamine, (1R,2S)-cis-1,2-indandiamine, (1S,2R)-cis-1,2-indandiamine, (R)-(-)-2-pyrrolidinemethanol and (S)-(+)-2-pyrrolidinemethanol.
Metals which may be represented by M include metals which are capable of catalysing transfer hydrogenation. Preferred metals include transition metals, more 10 preferably the metals in Group VIII of the Periodic Table, especially ruthenium, rhodium or iridium. When the metal is ruthenium it is preferably present in valence state II. When the metal is rhodium or iridium it is preferably present in valence state I when R3 is a neutral optionally substituted hydrocarbyl or a neutral optionally substituted perhalogenated hydrocarbyl ligand, and 'preferably present in valence state Ill when''R3 is an optionally substituted cyclopentadienyl ligand.
It is preferred that M, the metal, is rhodium present in valence state III and R3 is an optionally substituted cyclopentadienyf ligand.
Anionic groups which may be represented by Y include hydride,' hydroxy, hydrocarbyloxy, hydrocarbylamino and halogen groups. Preferably when a halogen is represented by Y, the halogen is chloride. When a hydrocarbyloxy or hydrocarbylamino group is represented by Y, the group may be derived from the deprotonation of the hydrogen donor utilised in the reaction.
Basic ligands which may be represented by Y include water, C~~ alcohols, C~_a primary or secondary amines, or the hydrogen donor which is present in the reaction system. A preferred basic ligand represented by Y is water.
Most preferably, A-E-B, R3 and Y are chosen so that the catalyst is chiral.
When such is the case, an enantiomerically and/or diastereomerically purified form is preferably employed. Such catalysts are most advantageously employed in asymmetric transfer hydrogenation processes.' In many embodiments, the chirality of the catalyst is derived from the nature of A-E-B.
An especially preferred catalyst of Formula (A) is of formula:
When either of A or B is present as a group represented by -NR4-, -NHR4, NR4R5, -NR8-, -NHRB or NR'R$ wherein R5 and R are as hereinbefore defined, and where R$ or R$
is a group represented by C(O)NR6R'°, C(S)NRsR'o, C(=NR'°)SR", C(=NR'°)OR", C(O)NR9R'~, C(S)NR9R'2, C(=NR'2)SR'3 or C(=NR'z)OR'3, R6 and R9 independently are often linear or branched C~_$alkyl, such as methyl, ethyl, isopropyl, C~_$cycloalkyl or aryl, for example phenyl, groups and R'o-'3 are often each independently hydrogen or linear or branched C~_aalkyl, such as methyl, ethyl, isopropyl, C,_acycloalkyl or aryl, for example phenyl, groups.
When B is present as a group represented by -OR', -SR','-PR'- or -PR'R9, R' and R9 independently are often linear or branched C,_8alkyl, such as methyl, ethyl, isopropyl, C~_$cycloalkyl or aryl, for example phenyl.
It will be recognised that the precise nature of A and B will be determined by whether A and/or B are formally bonded to the metal or are coordinated to the metal via a lone pair of electrons.
The groups A and B are connected by a linking group E. The linking group E
achieves a suitable conformation of A and B so as to allow both A and B to bond or coordinate to the metal, M. A and B are commonly linked through 2, 3 or 4 atoms. The atoms in E linking A and B may carry one or more substituents. The atoms in E, especially the atoms alpha to A or B, may be linked to A and B, in such a way as to form a heterocyclic ring, preferably a saturated ring, and particularly a 5, 6 or 7-membered ring.
Such a ring may be fused to one or more other rings. Often the atoms linking A
and B will be carbon atoms. Preferably, one or more of the carbon atoms linking A and B
will carry substituents in addition to A or B. Substituent groups include those which may substitute R5-' or R9-" as defined above. Advantageously, any such substituent groups are selected to be groups which do not coordinate with the metal, M. Preferred substituents include halogen, cyano, nitro, sulphonyl, hydrocarbyl, perhalogenated hydrocarbyl and heterocyclyl groups as defined above. Most preferred substituents are C~_6 alkyl groups, and phenyl groups. Most preferably, A and B are linked by two carbon atoms, and especially an optionally substituted ethyl moiety. When A and B are linked by two carbon atoms, the two carbon atoms linking A and B may comprise part of an aromatic or aliphatic cyclic group, particularly a 5, 6 or 7-membered ring. Such a ring may be fused to one or more other such rings. Particularly preferred are embodiments in which E
represents a 2 carbon atom separation and one or both of the carbon atoms carries an optionally substituted aryl group as defined above or E represents a 2 carbon atom separation which comprises a cyclopentane or cyclohexane ring, optionally fiused to a phenyl ring.
E preferably comprises part of a compound having at least one stereospecifiic centre. Where any or all of the 2, 3 or 4 atoms linking A and B are substituted so as to define at least one stereospecific centre on one or more of these atoms, it is preferred that at least one of the stereospecific centres be located at the atom adjacent to either group A
or B. When at least one such stereospecific centre is present, it is advantageously present in an enantiomerically purified state.
When B represents -O- or -OH, and the adjacent atom in E is carbon, it is preferred that B does not form part of a carboxylic group.
Compounds which may be represented by A-E-B, or from which A-E-B may be derived by deprotonation, are often aminoalcohols, including 4-aminoalkan-1-ols, 1-aminoalkan-4-ols, 3-aminoalkan-1-ols, 1-aminoalkan-3-ols, and especially 2-aminoalkan-1-ols, 1-aminoalkan-2-ols, 3-aminoalkan-2-ols and 2-aminoalkan-3-ols, and particularly 2-aminoethanols or 3-aminopropanols, or are diamines, including 1,4-diaminoalkanes, 1,3-diaminoalkanes, especially 1,2- or 2,3-diariiinoalkanes and particularly ethylenediamines. Further aminoalcohols that may be represented by A-E-B
are 2-aminocyclopentanols and 2-aminocyclohexanols, preferably fused to a phenyl ring.
Further diamines that may be represented by A-E-B are 1,2-diaminocycloperitanes and 1,2-diaminocyclohexanes, preferably fused to a phenyl ring. The amino groups may advantageously be N-tosylated. When a diamine is represented by A-E-B, preferably at least one amino group is N-tosylated. The aminoalcohols or diamines are advantageously substituted, especially on the linking group, E, by at feast one alkyl group, such as a C~_4-alkyl, and particularly a methyl, group or at least one aryl group, particularly a phenyl group.
Specific examples of compounds which can be represented by A-E-B and the protonated equivalents from which they may be derived are:
H3 ' .Ph Ph' -Ph Ph~ h Ph_ Ph HZN//~/~\OH HzN//~/\\NH-tosyl HzN/~/\NHz HzN/~~/NH-SOZ naphthyl ~~ N H-tosyl Ph CH3 Ph Ph PhCH CsHaOMe u /~ z~C6H40Me NHz HzN~ H HO NHz H ~ HZ HzN/ \NHz N
H OH
H N tosyl-HN
HZN HO z HzN
NHz OH NHz HO NHz Preferably, the enantiomerically and/or diastereomerically purified forms of these are used. Examples include (1 S,2R)-(+)-norephedrine, (1 R,2S)-(+)-cis-1-amino-2-indanol, (1 S,2R)-2-amino-1,2-diphenylethanol, (1 S,2R)-(-)-cis-1-amino-2-indanol, (1 R,2S)-(-)-norephedrine, (S)-(+)-2-amino-1-phenylethanol, (1R,2S)-2-amino-1,2-diphenylethanol, N-5 tosyl-(1R,2R)-1,2-diphenylethyfenediamine, N-tosyf-(1S,2S)-1,2-diphenylethylenediamine, (1R,2S)-cis-1,2-indandiamine, (1S,2R)-cis-1,2-indandiamine, (R)-(-)-2-pyrrolidinemethanol and (S)-(+)-2-pyrrolidinemethanol.
Metals which may be represented by M include metals which are capable of catalysing transfer hydrogenation. Preferred metals include transition metals, more 10 preferably the metals in Group VIII of the Periodic Table, especially ruthenium, rhodium or iridium. When the metal is ruthenium it is preferably present in valence state II. When the metal is rhodium or iridium it is preferably present in valence state I when R3 is a neutral optionally substituted hydrocarbyl or a neutral optionally substituted perhalogenated hydrocarbyl ligand, and 'preferably present in valence state Ill when''R3 is an optionally substituted cyclopentadienyl ligand.
It is preferred that M, the metal, is rhodium present in valence state III and R3 is an optionally substituted cyclopentadienyf ligand.
Anionic groups which may be represented by Y include hydride,' hydroxy, hydrocarbyloxy, hydrocarbylamino and halogen groups. Preferably when a halogen is represented by Y, the halogen is chloride. When a hydrocarbyloxy or hydrocarbylamino group is represented by Y, the group may be derived from the deprotonation of the hydrogen donor utilised in the reaction.
Basic ligands which may be represented by Y include water, C~~ alcohols, C~_a primary or secondary amines, or the hydrogen donor which is present in the reaction system. A preferred basic ligand represented by Y is water.
Most preferably, A-E-B, R3 and Y are chosen so that the catalyst is chiral.
When such is the case, an enantiomerically and/or diastereomerically purified form is preferably employed. Such catalysts are most advantageously employed in asymmetric transfer hydrogenation processes.' In many embodiments, the chirality of the catalyst is derived from the nature of A-E-B.
An especially preferred catalyst of Formula (A) is of formula:
H3C ~ CH3 Ph, H ~
NiR/H3C CHs Ph~N
CI
O
The preferred catalyst may be prepared in-situ preferably by combining a chiral bidentate nitrogen ligand with a Rh(III) metal complex containing a substituted cyclopentadienyl ligand. Preferably a solvent is present in this operation.
The solvent used may be anyone which does not adversely effect the formation of the catalyst.
These solvents include acetonitrile, ethylacetate, toluene, methanol, tetrahydrofuran, ethylmethyl ketone. Preferably the solvent is methanol.
Any suitable reductant may be used in the preferred embodiment of step (a), examples of reductants able to be used in this process include hydrogen donors including hydrogen, primary and secondary alcohols, primary and secondary amines, carboxylic acids and their esters and amine salts, readily dehydrogenatable hydrocarbons, clean reducing agents, and any combination thereof.
Primary and secondary alcohols which may be employed in the preferred embodiment of step (a) as hydrogen donors comprise commonly from 1 to 10 carbon atoms, preferably from 2 to 7 carbon atoms, and more preferably 3 or 4 carbon atoms.
Examples of primary and secondary alcohols which may be represented as hydrogen donors include methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol, butan-2-ol, cyclopentanol, cjrclohexanol, benzylalcohol, and menthol; especially propan-2-of and butan-2-ol.
Primary and secondary amines which may be employed in the preferred embodiment of step (a) as hydrogen donors comprise commonly from 1 to 20 carbon atoms, preferably from 2 to 14 carbon atoms, and more preferably 3 or 8 carbon atoms.
Examples of primary and secondary amines which may act as hydrogen donors include ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, hexylamine, diethylamine, dipropylamine, di-isopropylamine, dibutylamine, di-isobutylamine, dihexylamine, benzylamine, dibenzylamine and piperidine. When the hydrogen donor is an amine, primary amines are preferred, especially primary amines comprising a secondary alkyl group, particularly isopropylamine and isobutylamine.
Carboxylic acids and their esters which in a preferred embodiment of step (a) may act as hydrogen donors comprise commonly from 1 to 10 carbon atoms, preferably from 1 to 3 carbon atoms. In certain embodiments, the carboxylic acid is advantageously a beta-hydroxy-carboxylic acid. Esters may be derived from the carboxylic acid and a G~_~o alcohol. Examples of carboxylic acids which may be employed as hydrogen donors include formic acid, lactic acid, ascorbic acid and mandelic acid, especially formic acid.
In certain preferred embodiments, when a carboxylic acid is employed as hydrogen donor, at least some of the carboxylic acid is preferably present as salt, preferably an amine, ammonium or metal salt. Preferably, when a metal salt is present the metal is selected from the alkali or alkaline earth metals of the periodic table, and more preferably is sefecfied from the group 1 elements, such as lithium, sodium or potassium. Amines which may be used to form such salts include; primary, secondary and tertiary amines which comprise from 1 to 20 carbon atoms. Cyclic amines, both aromatic and non-aromatic , may also be used. Tertiary amines, especially trialkylamines, are preferred. Examples of amines which may be used to form salts include;
trimethylamine, triethylamine, di-isopropylethylamine and pyridine. The most preferred amine is triethylamine.
When at least some of the carboxylic acid is present as an amine salt, parkicularly when a mixture of formic acid and triethylamine is employed; the mole ratio of acid to amine is between 1:1 and 50:1 and preferably between 1:1 and 10:1, and most preferably about 5:2. When at least some of the carboxylic acid is present as a metal salt, particularly when a mixture of formic acid and a group I metal salt is employed, the mote ratio of acid to metal ions present is between 1:1 and 50:1 and preferably between 1:1 and 10:1, and most preferably about 2:1. The ratios of acid to salts may be maintained, during the course of the reaction by the addition of either component, but usually by the, addition of the carboxylic acid.
Readily dehydrogenatable hydrocarbons which may be employed in step (a) as hydrogen donors comprise hydrocarbons which have a propensity to aromatise or hydrocarbons which have a propensity to form highly conjugated systems.
Examples of readily dehydrogenatable hydrocarbons which may be employed by as hydrogen donors include cyclohexadiene, cyclohexene, tetralin, dihydrofuran and terpenes.
Clean reducing agents able to act as hydrogen donors comprise reducing agents with a high reduction potential, particularly those having a reduction potential relative to the standard hydrogen electrode of greater than about -0.1 eV, often greater than about -0.5eV, and preferably greater than about -1eV. Examples of suitable clean reducing agents include hydrazine and hydroxylamine.
The most preferred hydrogen donors in the preferred embodiment of step (a) are propan-2-ol, butan-2-ol, triethylammonium formate and a mixture of triethylammonium formate and formic acid.
Step (a) is preferably a stereospecific reaction. The predominant product may be either the R or S enantiomer of a compound of Formula (3) or Formula (7). The enantiomeric product of step (a) is preferably formed in at least 60%
enantiomeric excess (e.e.), more preferably in at least 80% e.e and especially in at least 90%
e.e.
NiR/H3C CHs Ph~N
CI
O
The preferred catalyst may be prepared in-situ preferably by combining a chiral bidentate nitrogen ligand with a Rh(III) metal complex containing a substituted cyclopentadienyl ligand. Preferably a solvent is present in this operation.
The solvent used may be anyone which does not adversely effect the formation of the catalyst.
These solvents include acetonitrile, ethylacetate, toluene, methanol, tetrahydrofuran, ethylmethyl ketone. Preferably the solvent is methanol.
Any suitable reductant may be used in the preferred embodiment of step (a), examples of reductants able to be used in this process include hydrogen donors including hydrogen, primary and secondary alcohols, primary and secondary amines, carboxylic acids and their esters and amine salts, readily dehydrogenatable hydrocarbons, clean reducing agents, and any combination thereof.
Primary and secondary alcohols which may be employed in the preferred embodiment of step (a) as hydrogen donors comprise commonly from 1 to 10 carbon atoms, preferably from 2 to 7 carbon atoms, and more preferably 3 or 4 carbon atoms.
Examples of primary and secondary alcohols which may be represented as hydrogen donors include methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol, butan-2-ol, cyclopentanol, cjrclohexanol, benzylalcohol, and menthol; especially propan-2-of and butan-2-ol.
Primary and secondary amines which may be employed in the preferred embodiment of step (a) as hydrogen donors comprise commonly from 1 to 20 carbon atoms, preferably from 2 to 14 carbon atoms, and more preferably 3 or 8 carbon atoms.
Examples of primary and secondary amines which may act as hydrogen donors include ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, hexylamine, diethylamine, dipropylamine, di-isopropylamine, dibutylamine, di-isobutylamine, dihexylamine, benzylamine, dibenzylamine and piperidine. When the hydrogen donor is an amine, primary amines are preferred, especially primary amines comprising a secondary alkyl group, particularly isopropylamine and isobutylamine.
Carboxylic acids and their esters which in a preferred embodiment of step (a) may act as hydrogen donors comprise commonly from 1 to 10 carbon atoms, preferably from 1 to 3 carbon atoms. In certain embodiments, the carboxylic acid is advantageously a beta-hydroxy-carboxylic acid. Esters may be derived from the carboxylic acid and a G~_~o alcohol. Examples of carboxylic acids which may be employed as hydrogen donors include formic acid, lactic acid, ascorbic acid and mandelic acid, especially formic acid.
In certain preferred embodiments, when a carboxylic acid is employed as hydrogen donor, at least some of the carboxylic acid is preferably present as salt, preferably an amine, ammonium or metal salt. Preferably, when a metal salt is present the metal is selected from the alkali or alkaline earth metals of the periodic table, and more preferably is sefecfied from the group 1 elements, such as lithium, sodium or potassium. Amines which may be used to form such salts include; primary, secondary and tertiary amines which comprise from 1 to 20 carbon atoms. Cyclic amines, both aromatic and non-aromatic , may also be used. Tertiary amines, especially trialkylamines, are preferred. Examples of amines which may be used to form salts include;
trimethylamine, triethylamine, di-isopropylethylamine and pyridine. The most preferred amine is triethylamine.
When at least some of the carboxylic acid is present as an amine salt, parkicularly when a mixture of formic acid and triethylamine is employed; the mole ratio of acid to amine is between 1:1 and 50:1 and preferably between 1:1 and 10:1, and most preferably about 5:2. When at least some of the carboxylic acid is present as a metal salt, particularly when a mixture of formic acid and a group I metal salt is employed, the mote ratio of acid to metal ions present is between 1:1 and 50:1 and preferably between 1:1 and 10:1, and most preferably about 2:1. The ratios of acid to salts may be maintained, during the course of the reaction by the addition of either component, but usually by the, addition of the carboxylic acid.
Readily dehydrogenatable hydrocarbons which may be employed in step (a) as hydrogen donors comprise hydrocarbons which have a propensity to aromatise or hydrocarbons which have a propensity to form highly conjugated systems.
Examples of readily dehydrogenatable hydrocarbons which may be employed by as hydrogen donors include cyclohexadiene, cyclohexene, tetralin, dihydrofuran and terpenes.
Clean reducing agents able to act as hydrogen donors comprise reducing agents with a high reduction potential, particularly those having a reduction potential relative to the standard hydrogen electrode of greater than about -0.1 eV, often greater than about -0.5eV, and preferably greater than about -1eV. Examples of suitable clean reducing agents include hydrazine and hydroxylamine.
The most preferred hydrogen donors in the preferred embodiment of step (a) are propan-2-ol, butan-2-ol, triethylammonium formate and a mixture of triethylammonium formate and formic acid.
Step (a) is preferably a stereospecific reaction. The predominant product may be either the R or S enantiomer of a compound of Formula (3) or Formula (7). The enantiomeric product of step (a) is preferably formed in at least 60%
enantiomeric excess (e.e.), more preferably in at least 80% e.e and especially in at least 90%
e.e.
The preferred product of step (a) is a compound of Formula (9):
R~ ON
R')n / /
Formula (9) where R', RZ and n are as defined for Formula (5).
Step (a) of the process may be performed in the presence of an organic solvent or mixture of organic solvents that is compatible with the reagents employed.
These solvents include N,N~dimethylformamide, acetonitrile, tetrahydrofuran and C,~
alcohols such as methanol.
Step (a) of the process is performed at a temperature where the reactants and catalyst are sufficiently stable for the reaction to proceed to a significant degree.
Preferably step (a) of the process is carried out at a temperature below 35°C and more preferably in a range of from 0°C to 20°C.
Step (a) of the process is advantageously allowed to proceed to at least 90%
conversion, more preferably to at least 95% conversion.
The reaction time of step (a) of the process of the present invention will depend on a number of factors, for example the reagent concentrations, the relative amounts of reagents, the reaction temperature and particularly the presence and nature of any catalyst employed. Typical reaction times, in addition to the reagent addition times, range from 15 minute to 20 hours, with reaction times of 30 minutes to 10 hours being common.
Preferably, the process of step (a) is carried out under a substantially inert atmosphere, for example nitrogen or argon.
Compounds of Formula (2) and (6) may be purchased or prepared by methods well known in the art from commercially available starting materials. For example, 1-acetonaphthone may be purchased from Aldrich.
The leaving group donor in step (b) may be any compound known in the art able to react with the hydroxyl on compounds of Formula (3) and Formula (7) to give a species which may be displaced by ammonia and so yield a compound of Formula (1 ) and Formula (5).
The leaving group donor preferably forms an ester or a sulphonate bond with the hydroxyl group, especially a sulphonate bond.
Thus, the preferred leaving group donor is a compound of formula R'4S02X, where R'4 is an optionally substituted alkyl, optionally substituted aryl, such as phenyl or an optionally substituted heteroaryl group and X is a halogen.
R~ ON
R')n / /
Formula (9) where R', RZ and n are as defined for Formula (5).
Step (a) of the process may be performed in the presence of an organic solvent or mixture of organic solvents that is compatible with the reagents employed.
These solvents include N,N~dimethylformamide, acetonitrile, tetrahydrofuran and C,~
alcohols such as methanol.
Step (a) of the process is performed at a temperature where the reactants and catalyst are sufficiently stable for the reaction to proceed to a significant degree.
Preferably step (a) of the process is carried out at a temperature below 35°C and more preferably in a range of from 0°C to 20°C.
Step (a) of the process is advantageously allowed to proceed to at least 90%
conversion, more preferably to at least 95% conversion.
The reaction time of step (a) of the process of the present invention will depend on a number of factors, for example the reagent concentrations, the relative amounts of reagents, the reaction temperature and particularly the presence and nature of any catalyst employed. Typical reaction times, in addition to the reagent addition times, range from 15 minute to 20 hours, with reaction times of 30 minutes to 10 hours being common.
Preferably, the process of step (a) is carried out under a substantially inert atmosphere, for example nitrogen or argon.
Compounds of Formula (2) and (6) may be purchased or prepared by methods well known in the art from commercially available starting materials. For example, 1-acetonaphthone may be purchased from Aldrich.
The leaving group donor in step (b) may be any compound known in the art able to react with the hydroxyl on compounds of Formula (3) and Formula (7) to give a species which may be displaced by ammonia and so yield a compound of Formula (1 ) and Formula (5).
The leaving group donor preferably forms an ester or a sulphonate bond with the hydroxyl group, especially a sulphonate bond.
Thus, the preferred leaving group donor is a compound of formula R'4S02X, where R'4 is an optionally substituted alkyl, optionally substituted aryl, such as phenyl or an optionally substituted heteroaryl group and X is a halogen.
It is especially preferred that R'4 is optionally substituted C~~alkyl, particularly methyl.
X is preferably chloride.
Preferably the leaving group donor is methanesulphonyl chloride.
Step (b) of the process may be performed in the presence of an organic solvent or mixture of organic solvents which is unreactive towards the reagents employed.
Examples of suitable solvents include toluene, tetrahydrofuran and acetonitrile.
Step (b) of the process is preferably perfiormed at a temperature in the range of from -50°C to 50°C and more preferably in a range of from -20°C to 20°C. It is especially preferred that step (b) is carried out at a temperature in the range of from -5°C to 5°C.
Step (b) of the process is advantageously allowed to proceed to at least 90%
conversion, more preferably to at least 95% conversion.
The reaction time of step (b) of the process of the present invention will depend on a number of factors, for example the reagent concentrations! the relative ar~nourits of reagents and particularly the reaction temperature. Typical reaction times, in addition to the reagent addition times, range from 15 minute to 20 hours, with reaction times of 30 minutes to 10 hours being common, Preferably, the process of step (b) is carried out under a substantially inert atmosphere, for example nitrogen or argon.
When the compounds of Formula (3) and Formula (7) are specific enantiomers step (b) is preferably carried out without any significant racemisation.
In step (c) of the process ammonia may be in any form able to react with compounds of Formula (4) and Formula (8) to give the corresponding amine.
Preferably, ammonia is present as an aqueous solution.
Step (c) of the process may be performed in the presence of an organic solvent or mixture of organic solvents which is unreactive towards the reagents employed.
Examples of suitable solvents include: tetrahydrofuran, toluene, acetonitrile, liquid ammonia and water.
Step (c) of the process is preferably performed at a temperature in the range of from -50°C to 200°C and more preferably in the range of from 0°C to180°C. It is especially preferred that step (b) is carried out in the range of from 40°C to 140°C.
Step (c) of the process is preferably performed under a pressure in the range of from 1 to 100 bar and more preferably in the range of from 1 to 10 bar.
Step (c) of the process is advantageously allowed to proceed to at least 90%
conversion, more preferably to at least 95°l° conversion.
The reaction time of step (c) of the process of the present invention will depend on a number of factors, for example the reagent concentrations, the relative amounts of reagents and particularly the pressure and reaction temperature. Typical reaction times, in addition to the reagent addition times, range from 15 minute to 20 hours, with reaction times of 30 minutes to 10 hours being common.
When the compound of Formula (4) or of Formula (8) is a specific enantiomer then step (c) is preferably carried out without any significant racemisation.
When the compound of Formula (1 ) or of Formula (5), formed by step (c), is a specific enantiomer then preferably it is formed in at least 60% enantiomeric excess (e.e.), 5 more preferably in at least 80% e.e and especially in at least 90% e.e.
If the compound of Formula (1 ) or of Formula (5) is a sterioisomer it may be further purified, if necessary, by any method known in the art such as a diastereomeric salt resolution to enantioenrich the desired amine.
The compound of Formula (1 ) or of Formula (5) purified by diastereomeric salt 10 resolution is preferably in at least 90% enantiomeric excess (e.e.), more preferably in at least 95% e.e and especially is in greater than 99% e.e.
A preferred embodiment of the first aspect of the invention provides a process for the preparation of a compound of Formula (10):
H3C ,,, NHz / /
which comprises the steps:
Formula (10) (a) reducing a compound of Formula (11 ):
/ /
Formula (11 ) to a compound of Formula (12):
/ /
Formula (12) (b) reacting a compound of Formula (12) with a compound of formula R3SOzX, in the presence of a base, to give a compound of Formula (13);
\ \
/ /
Formula (13) wherein:
R3 is optionally substituted C~~alkyl; and X is halogen:
(c) reacting a compound of Formula (13) with ammonia to give a compound of Formula (10).
Structural and process preferences for the preferred embodiment of the first aspect of the invention are as described above.
If is especially preferred that step (a) of this preferred embodiment is carried out in the presence of a catalyst of Formula (A) as described and preferred above.
When further purification of the compound of Formula (10) is required it may be achieved by any means known in the art. These methods include a diastereomeric salt resolution to enantioenrich the desired amine. Preferably the diastereomeric salt resolution employs (L)-tartaric acid or (L)-chloropropionic acid and more preferably (L)-chloropropionic acid.
The compound of Formula (10) purified by diastereomeric salt resolution is preferably in at least 90% enantiomeric excess (e.e.), more preferably in at least 95% e.e and especially is in greater than 99% e.e.
A second aspect of the invention proves a process for the preparation of a stereoisomer of a compound of Formula (14):
RZ OH
\ \
R1)n / /
Formula (14) wherein R', R2 and n are as described and preferred in the first aspect of the invention, which comprises the transfer hydrogenation of a compound of Formula (6):
Rz O
\ \
R')n / /
Formula (6) by a hydrogen donor in the presence of a catalyst of Formula (A):
eEv A~ ~B
s 1..,3 YY
Formula (A) wherein the catalyst of Formula (A) and the hydrogen donor are as described and preferred in the first aspect of the invention.
A third aspect of the invention provides a process for the diastereomeric salt resolution of (S)-1-naphthylethylamine which comprises mixing (S)-1-naphthylethylamine with (2R,3R)-tartaric acid or (S)-chloropropionic acid, preferably (S)-chloropropionic acid, to form the corresponding diastereomeric salt. The diastereomeric salt so formed may be separated from the reaction mixture using established techniques such as filtration. Once isolated the diastereomeric salt may be further purified by repeating the process of the third aspect of the invention. The isolated diastereomeric salt may also be converted into other salt forms by established techniques known in the art such as ion-exchange chromatography and dialysis.
A fourth aspect of the invention provides a diastereomeric salt of (S)-1 naphthylethylamine with (2R,3R)-tartaric acid or (S)-chloropropionic acid, preferably (S) chloropropionic acid.
A fifth aspect of the invention provides a compound of Formula (15):
RZ OSO~CH3 \ \
R~)n / /
Formula (15) wherein R~, R2 and n are as preferred in the first aspect of the invention.
Preferably the compound of Formula (15) is of Formula (16):
\ \
Formula (16) Compounds of Formula (15) may be formed by reacting a mesyl donor, such as methanesulfonyl chloride, with a compound of Formula (7) in the presence of an organic base, particularly triethylamine.
Many of the compounds described above may exist in the form of a salt. These salts are included within the scope of the present inventions.
The compounds described above may be converted to the salt form using known techniques.
The compounds described herein may exist in tautomeric forms other than those shown in this specification. These tautomers are also included within the scope of the present inventions.
The invention is illustrated, without limitation, by the following examples.
Example 1 Stage 1 CH p CH3 OH
Rh-(S,S,S)-CSDPEN \ \
\ \
/ / MeOH, r.t., ~ /
S/C=300/1, [S]=3M
Sta a 9 Selection of the Catalyst Sta a 1 a Selection of the ligand Ten mono-tosylated diamine ligands were screened to determine which would give the optimum stereo selective reduction of 1'-acetonaphthone to (R)-1-acetonaphthylethylalcohol.
In the experiments equivalents of [Rh pentamethylcyclopentadienylCl2]z and the various mono-tosylated diamine ligands were added to tetrahydrofuran (THF) at room temperature with stirring under a low nitrogen purge for 30 mins. These catalyst solutions were added to 1'-acetonaphthone in a ratio of substrate to catalyst of 200 to 1. Formic acid (hydrogen donor) was then added slowly to the reaction mixtures, at a ratio of 6 tot formic acid to 1'-acetonaphthone. The reaction mixtures were left at room temperature for under nitrogen for 16 hours. At the end of this time the products were analysed by HPLC.
The conditions were as follows:
Column: Chiralcel OD (25cmx4.6mm) Eluent: Hexane/EtOH (absolute) : 92.5/7.5 Flov~i rate: 1 ml_/min Detection: UV, 254 nm Temperature:30°C
The ligands evaluated and the enantiomeric excess (e.e.) of the (R) enantiomer product are shown below in Table 1:
Table 1 Ligand Structure e.e. (%) o Ph N-O \ / '70 ~
Ph ~
NHZ
Ph NHZ
~ 6 NH
Ph O
\ /
C Pn,, 19 NH-I \
Ph__NHZ O
C!
o D -Pn, 36 NH-.o \ /
~
Ph O _ E Ph N-S \ / NOz 74 ~
~ O
,, Ph "NHZ
Me0 F P"~NH- - 54 Ph NHZ CI
O _ Ph N-S \ / CI 51 ~ O
Ph "NHZ
O _ H Ph N-S ~ / OMe 41 O
Ph ~~1 NHz o ! Ph N-O \ / F
Ph "NNZ
NHTs 24 ''' NHz From the table above, it can be seen that the catalyst comprising ligand B ((S,S,S) CS-DPEN, ((S,S,S)-N-(2-Amino-1,2-diphenyl-ethyl)-C-(7,7-dimethyl-2 oxo-bicyclo[2.2.1]hept-1-yl)methanesulfonamide)) (CS-DPEN) is the most selective for 5 (R)-1-acetonaphthylethylalcohol.
Sta a 1 b Screening for the o~~timum solvent The protocol of stage 1 (a) was repeated using the CS-DPEN ligand (ligand B) in 10 all cases but with tetrahydrofuran being replaced by the solvents as shown in Table 2.
The optical purity of the products formed was determined using HPLC as described in stage 1 (a). Results are shown in Table 2 in terms of the enantiomeric excess (e.e.) of the (R) enantiomer of 1-acetonaphthylethylalcohol.
X is preferably chloride.
Preferably the leaving group donor is methanesulphonyl chloride.
Step (b) of the process may be performed in the presence of an organic solvent or mixture of organic solvents which is unreactive towards the reagents employed.
Examples of suitable solvents include toluene, tetrahydrofuran and acetonitrile.
Step (b) of the process is preferably perfiormed at a temperature in the range of from -50°C to 50°C and more preferably in a range of from -20°C to 20°C. It is especially preferred that step (b) is carried out at a temperature in the range of from -5°C to 5°C.
Step (b) of the process is advantageously allowed to proceed to at least 90%
conversion, more preferably to at least 95% conversion.
The reaction time of step (b) of the process of the present invention will depend on a number of factors, for example the reagent concentrations! the relative ar~nourits of reagents and particularly the reaction temperature. Typical reaction times, in addition to the reagent addition times, range from 15 minute to 20 hours, with reaction times of 30 minutes to 10 hours being common, Preferably, the process of step (b) is carried out under a substantially inert atmosphere, for example nitrogen or argon.
When the compounds of Formula (3) and Formula (7) are specific enantiomers step (b) is preferably carried out without any significant racemisation.
In step (c) of the process ammonia may be in any form able to react with compounds of Formula (4) and Formula (8) to give the corresponding amine.
Preferably, ammonia is present as an aqueous solution.
Step (c) of the process may be performed in the presence of an organic solvent or mixture of organic solvents which is unreactive towards the reagents employed.
Examples of suitable solvents include: tetrahydrofuran, toluene, acetonitrile, liquid ammonia and water.
Step (c) of the process is preferably performed at a temperature in the range of from -50°C to 200°C and more preferably in the range of from 0°C to180°C. It is especially preferred that step (b) is carried out in the range of from 40°C to 140°C.
Step (c) of the process is preferably performed under a pressure in the range of from 1 to 100 bar and more preferably in the range of from 1 to 10 bar.
Step (c) of the process is advantageously allowed to proceed to at least 90%
conversion, more preferably to at least 95°l° conversion.
The reaction time of step (c) of the process of the present invention will depend on a number of factors, for example the reagent concentrations, the relative amounts of reagents and particularly the pressure and reaction temperature. Typical reaction times, in addition to the reagent addition times, range from 15 minute to 20 hours, with reaction times of 30 minutes to 10 hours being common.
When the compound of Formula (4) or of Formula (8) is a specific enantiomer then step (c) is preferably carried out without any significant racemisation.
When the compound of Formula (1 ) or of Formula (5), formed by step (c), is a specific enantiomer then preferably it is formed in at least 60% enantiomeric excess (e.e.), 5 more preferably in at least 80% e.e and especially in at least 90% e.e.
If the compound of Formula (1 ) or of Formula (5) is a sterioisomer it may be further purified, if necessary, by any method known in the art such as a diastereomeric salt resolution to enantioenrich the desired amine.
The compound of Formula (1 ) or of Formula (5) purified by diastereomeric salt 10 resolution is preferably in at least 90% enantiomeric excess (e.e.), more preferably in at least 95% e.e and especially is in greater than 99% e.e.
A preferred embodiment of the first aspect of the invention provides a process for the preparation of a compound of Formula (10):
H3C ,,, NHz / /
which comprises the steps:
Formula (10) (a) reducing a compound of Formula (11 ):
/ /
Formula (11 ) to a compound of Formula (12):
/ /
Formula (12) (b) reacting a compound of Formula (12) with a compound of formula R3SOzX, in the presence of a base, to give a compound of Formula (13);
\ \
/ /
Formula (13) wherein:
R3 is optionally substituted C~~alkyl; and X is halogen:
(c) reacting a compound of Formula (13) with ammonia to give a compound of Formula (10).
Structural and process preferences for the preferred embodiment of the first aspect of the invention are as described above.
If is especially preferred that step (a) of this preferred embodiment is carried out in the presence of a catalyst of Formula (A) as described and preferred above.
When further purification of the compound of Formula (10) is required it may be achieved by any means known in the art. These methods include a diastereomeric salt resolution to enantioenrich the desired amine. Preferably the diastereomeric salt resolution employs (L)-tartaric acid or (L)-chloropropionic acid and more preferably (L)-chloropropionic acid.
The compound of Formula (10) purified by diastereomeric salt resolution is preferably in at least 90% enantiomeric excess (e.e.), more preferably in at least 95% e.e and especially is in greater than 99% e.e.
A second aspect of the invention proves a process for the preparation of a stereoisomer of a compound of Formula (14):
RZ OH
\ \
R1)n / /
Formula (14) wherein R', R2 and n are as described and preferred in the first aspect of the invention, which comprises the transfer hydrogenation of a compound of Formula (6):
Rz O
\ \
R')n / /
Formula (6) by a hydrogen donor in the presence of a catalyst of Formula (A):
eEv A~ ~B
s 1..,3 YY
Formula (A) wherein the catalyst of Formula (A) and the hydrogen donor are as described and preferred in the first aspect of the invention.
A third aspect of the invention provides a process for the diastereomeric salt resolution of (S)-1-naphthylethylamine which comprises mixing (S)-1-naphthylethylamine with (2R,3R)-tartaric acid or (S)-chloropropionic acid, preferably (S)-chloropropionic acid, to form the corresponding diastereomeric salt. The diastereomeric salt so formed may be separated from the reaction mixture using established techniques such as filtration. Once isolated the diastereomeric salt may be further purified by repeating the process of the third aspect of the invention. The isolated diastereomeric salt may also be converted into other salt forms by established techniques known in the art such as ion-exchange chromatography and dialysis.
A fourth aspect of the invention provides a diastereomeric salt of (S)-1 naphthylethylamine with (2R,3R)-tartaric acid or (S)-chloropropionic acid, preferably (S) chloropropionic acid.
A fifth aspect of the invention provides a compound of Formula (15):
RZ OSO~CH3 \ \
R~)n / /
Formula (15) wherein R~, R2 and n are as preferred in the first aspect of the invention.
Preferably the compound of Formula (15) is of Formula (16):
\ \
Formula (16) Compounds of Formula (15) may be formed by reacting a mesyl donor, such as methanesulfonyl chloride, with a compound of Formula (7) in the presence of an organic base, particularly triethylamine.
Many of the compounds described above may exist in the form of a salt. These salts are included within the scope of the present inventions.
The compounds described above may be converted to the salt form using known techniques.
The compounds described herein may exist in tautomeric forms other than those shown in this specification. These tautomers are also included within the scope of the present inventions.
The invention is illustrated, without limitation, by the following examples.
Example 1 Stage 1 CH p CH3 OH
Rh-(S,S,S)-CSDPEN \ \
\ \
/ / MeOH, r.t., ~ /
S/C=300/1, [S]=3M
Sta a 9 Selection of the Catalyst Sta a 1 a Selection of the ligand Ten mono-tosylated diamine ligands were screened to determine which would give the optimum stereo selective reduction of 1'-acetonaphthone to (R)-1-acetonaphthylethylalcohol.
In the experiments equivalents of [Rh pentamethylcyclopentadienylCl2]z and the various mono-tosylated diamine ligands were added to tetrahydrofuran (THF) at room temperature with stirring under a low nitrogen purge for 30 mins. These catalyst solutions were added to 1'-acetonaphthone in a ratio of substrate to catalyst of 200 to 1. Formic acid (hydrogen donor) was then added slowly to the reaction mixtures, at a ratio of 6 tot formic acid to 1'-acetonaphthone. The reaction mixtures were left at room temperature for under nitrogen for 16 hours. At the end of this time the products were analysed by HPLC.
The conditions were as follows:
Column: Chiralcel OD (25cmx4.6mm) Eluent: Hexane/EtOH (absolute) : 92.5/7.5 Flov~i rate: 1 ml_/min Detection: UV, 254 nm Temperature:30°C
The ligands evaluated and the enantiomeric excess (e.e.) of the (R) enantiomer product are shown below in Table 1:
Table 1 Ligand Structure e.e. (%) o Ph N-O \ / '70 ~
Ph ~
NHZ
Ph NHZ
~ 6 NH
Ph O
\ /
C Pn,, 19 NH-I \
Ph__NHZ O
C!
o D -Pn, 36 NH-.o \ /
~
Ph O _ E Ph N-S \ / NOz 74 ~
~ O
,, Ph "NHZ
Me0 F P"~NH- - 54 Ph NHZ CI
O _ Ph N-S \ / CI 51 ~ O
Ph "NHZ
O _ H Ph N-S ~ / OMe 41 O
Ph ~~1 NHz o ! Ph N-O \ / F
Ph "NNZ
NHTs 24 ''' NHz From the table above, it can be seen that the catalyst comprising ligand B ((S,S,S) CS-DPEN, ((S,S,S)-N-(2-Amino-1,2-diphenyl-ethyl)-C-(7,7-dimethyl-2 oxo-bicyclo[2.2.1]hept-1-yl)methanesulfonamide)) (CS-DPEN) is the most selective for 5 (R)-1-acetonaphthylethylalcohol.
Sta a 1 b Screening for the o~~timum solvent The protocol of stage 1 (a) was repeated using the CS-DPEN ligand (ligand B) in 10 all cases but with tetrahydrofuran being replaced by the solvents as shown in Table 2.
The optical purity of the products formed was determined using HPLC as described in stage 1 (a). Results are shown in Table 2 in terms of the enantiomeric excess (e.e.) of the (R) enantiomer of 1-acetonaphthylethylalcohol.
15 Table 2 Solvent e.e. (%) Acrylonitriie 76 Ethylacetate 84 Toluene 84 Methanol g5 Ethylmethyl ketone 80 Table 2 shows that the solvent used in forming the catalyst has an effect on the stereo-selectivity of the reaction the best result being obtained with methanol.
20 Based on the results shown in Table 1 and Table 2 the (S,S,S)-CS-DPEN
ligand was chosen as the catalyst ligand of choice and methanol was chosen as the preferred solvent for catalyst formation.
Stage 2 Rh-(S,S,S)-CSDpEN \ \
\ \
MeO~i, r.t., ~ /
S/C=300/1, [S]=3M
Stage 2 a) Preparation of the Catalyst Solution The catalyst was formed by adding [Rh pentamethylcyclopentadienylCfzJ~
(60.5 mg), (S,S,S)-CS-DPEN (83.7 mg) and methanol (20 ml) to a round bottom-flask with stirring under a low nitrogen purge for 30 mins.
Stage 2(b) 1'-Acetonaphthone (10 g) was added to a 100 ml jacketed vessel and stirred for minutes. The reactor temperature was set at 20°C and the vessel was purged with nitrogen by continuous sparge and stirred throughout the reaction. One quarter of the catalyst solution prepared in stage 2(a) was added to the reaction vessel and then 13.8 ml of a mixture of triethylamine/formic acid (ratio 2:5) was added at a rate of 2.3mf/min. One and a half hours after the first addition of the catalyst solution a further aliquot of one quarter of the catalyst solution was added to the reaction mixture and this was repeated after three and four and a half hours. The reaction mixture was allowed to stir at 20°C far 12-18 hours until complete and then water (20m1) was added in portions allowing the reaction temperature to warm to 20°C in between additions. This mixture was transferred to a separating vessel at room temperature and toluene (40 ml) was added. The mixture was stirred vigorously for 30 minutes and then allowed to settle for 30 minutes., The organic layer was taken and brine (10%, 20m1) was added. The mixture was again stirred vigorously for 30 minutes and then allowed to settle for a further 30 minutes.
The extraction with brine was repeated two more times and then the organic solution was concentrated down to 20% volume by rotary evaporation. The reaction proceeded with greater than 99% conversion to give a product of 94.5% e.e.
Sfia a 3 CH3 OH CH3 OMs MsCI (2eq.) \ \ \ \
Et3N (2 eq.) / ~ toluene, o~C
The product of stage 2 (10.1 g in 60m1 of toluene) was added to a reaction vessel and stirred under nitrogen. The reaction mixture was cooled to -5°C and triethylamine (16.41 ml) was added dropwise. Methanesulfonyl chloride(9.28 ml) was then added dropwise while maintaining the temperature of the reaction mixture below 0°C. The reaction mixture was then allowed to warm to room temperature and stirred for a further 2.5 hours. The reaction mixture was then filtered to remove triethylamine hydrochloride and the resultant toluene solution was used directly in Stage 4.
Stagie 4 CH3 OMs CH3 ,~, NHS
\ \ \ \
toluene, 87~C ~ / /
3 bar Aqueous ammonia (30%, 27.7 ml) was added to a Parr reactor. The toluene solution of the product of stage 3 was added and the reactor was sealed and heated to 87°C at 3 bar and allowed to react for 5 hours. At the end of this time the pressure was released and the toluene solution was separated and then evaporated to dryness to yield the title product, (S)-1-naphthylethylamine, in 94% e.e. (S)-1-naphthylethylamine was assessed using the HPLC protocol as described in stage 1 (a) where (S)-1-Naphthylethylamine eluted at 12.0 minutes and (R)-1-Naphthylethylamine eluted at 5.9 minutes.
Sta a 5 Diastereomeric salt resolution Stage 5a Selection of the salt acid Acids were screened to see which, in a diastereomeric salt resolution, would yield (S)-1-naphthylethylamine in the greatest optical purity. The following acids were evaluated; (L)-malic acid, (L)-mandelic acid, (L)-tartaric acid, (L)-chloropropionic acid (LCPA), (L)-camphor acid and (L)- camphorsulfonic acid. Each acid (except LCPA) was screened in a range of 4 solvents: ethanol/water, methanol/water, isopropyl/water, ethyl acetate.
(S)-1-Naphthylethylamine of 94% e.e., as produced in stage 4 was mixed with each of the above acids and the crystals which formed were collected and were analysed as described in stage 1 (a) and stage 4.
Acid Solvent Crystals e.e(%) (L)-malic acid ethanol /water Yes 94 methanol/water No isopropyl alcohol/waterYes 94 ethylacetate No (L)-Tartaric acid ethanol /water Yes 97 methanollwater Yes 94 isopropyl alcohol/waterYes 95 ethylacetate Yes 94 (L)-Chloropropionicethanol/water Yes >99 acid (LCPA) (L)-Mandelic acid ethanol /water Yes 95 methanol/water Yes ~ 94 isopropyl alcohol/waterYes 94 ethylacetate Yes 94 (L)-camphor acid ethanol /water Yes 94 methanol/water Yes 94 isopropyl alcohol/waterYes 94 ethylacetate No (L)-camphorsulfonicethanol /water Yes 94 acid methanol/water No isopropyl alcohoUwaterNo ethylacetate No A significant improvement in e.e. was only observed with (L)-tartaric acid (97%) and with LCPA (>99%) in ethanol/water.
Sta a 5 b Formation of the salt ci CH3 ~~NHz CH~COOH CH3 ,,.NHZHOOC~CH
/ / EtOH/H~0:10/90 ~ / /
A mixture of ethanol (1.68 ml) and water (15.1 ml) was added with stirring to the product of stage 4. (L)-Chloropropionic acid (6.38 g, 1 equivalent of the product of step 4) was then added dropwise to the stirred mixture. The mixture was then heated to 60°C
and stirred for a further 30 minutes. The reaction mixture was cooled to room temperature and then concentrated to 50% by volume in a rotary evaporator and then allowed to settle until the precipitated salt is fully formed.
Ste 5 c Formation of the Free Amine c1 CH ~
,~, NHa HOOC~CH3 CH ~~ NHZ
NaOH
\ \ ~ ~ \ \
/ / toluene / /
The salt from stage 5 (b) (4.53g) was dissolved in 25 ml of 5M NaOH. Toluene (25m1) was added to this solution while maintaining the pH above 10 by the addition of additional NaOH. The mixture was allowed to settle and the toluene solution was concentrated to dryness to yield the title product, as a yellow liquid, in greater than 99%
e.e.
20 Based on the results shown in Table 1 and Table 2 the (S,S,S)-CS-DPEN
ligand was chosen as the catalyst ligand of choice and methanol was chosen as the preferred solvent for catalyst formation.
Stage 2 Rh-(S,S,S)-CSDpEN \ \
\ \
MeO~i, r.t., ~ /
S/C=300/1, [S]=3M
Stage 2 a) Preparation of the Catalyst Solution The catalyst was formed by adding [Rh pentamethylcyclopentadienylCfzJ~
(60.5 mg), (S,S,S)-CS-DPEN (83.7 mg) and methanol (20 ml) to a round bottom-flask with stirring under a low nitrogen purge for 30 mins.
Stage 2(b) 1'-Acetonaphthone (10 g) was added to a 100 ml jacketed vessel and stirred for minutes. The reactor temperature was set at 20°C and the vessel was purged with nitrogen by continuous sparge and stirred throughout the reaction. One quarter of the catalyst solution prepared in stage 2(a) was added to the reaction vessel and then 13.8 ml of a mixture of triethylamine/formic acid (ratio 2:5) was added at a rate of 2.3mf/min. One and a half hours after the first addition of the catalyst solution a further aliquot of one quarter of the catalyst solution was added to the reaction mixture and this was repeated after three and four and a half hours. The reaction mixture was allowed to stir at 20°C far 12-18 hours until complete and then water (20m1) was added in portions allowing the reaction temperature to warm to 20°C in between additions. This mixture was transferred to a separating vessel at room temperature and toluene (40 ml) was added. The mixture was stirred vigorously for 30 minutes and then allowed to settle for 30 minutes., The organic layer was taken and brine (10%, 20m1) was added. The mixture was again stirred vigorously for 30 minutes and then allowed to settle for a further 30 minutes.
The extraction with brine was repeated two more times and then the organic solution was concentrated down to 20% volume by rotary evaporation. The reaction proceeded with greater than 99% conversion to give a product of 94.5% e.e.
Sfia a 3 CH3 OH CH3 OMs MsCI (2eq.) \ \ \ \
Et3N (2 eq.) / ~ toluene, o~C
The product of stage 2 (10.1 g in 60m1 of toluene) was added to a reaction vessel and stirred under nitrogen. The reaction mixture was cooled to -5°C and triethylamine (16.41 ml) was added dropwise. Methanesulfonyl chloride(9.28 ml) was then added dropwise while maintaining the temperature of the reaction mixture below 0°C. The reaction mixture was then allowed to warm to room temperature and stirred for a further 2.5 hours. The reaction mixture was then filtered to remove triethylamine hydrochloride and the resultant toluene solution was used directly in Stage 4.
Stagie 4 CH3 OMs CH3 ,~, NHS
\ \ \ \
toluene, 87~C ~ / /
3 bar Aqueous ammonia (30%, 27.7 ml) was added to a Parr reactor. The toluene solution of the product of stage 3 was added and the reactor was sealed and heated to 87°C at 3 bar and allowed to react for 5 hours. At the end of this time the pressure was released and the toluene solution was separated and then evaporated to dryness to yield the title product, (S)-1-naphthylethylamine, in 94% e.e. (S)-1-naphthylethylamine was assessed using the HPLC protocol as described in stage 1 (a) where (S)-1-Naphthylethylamine eluted at 12.0 minutes and (R)-1-Naphthylethylamine eluted at 5.9 minutes.
Sta a 5 Diastereomeric salt resolution Stage 5a Selection of the salt acid Acids were screened to see which, in a diastereomeric salt resolution, would yield (S)-1-naphthylethylamine in the greatest optical purity. The following acids were evaluated; (L)-malic acid, (L)-mandelic acid, (L)-tartaric acid, (L)-chloropropionic acid (LCPA), (L)-camphor acid and (L)- camphorsulfonic acid. Each acid (except LCPA) was screened in a range of 4 solvents: ethanol/water, methanol/water, isopropyl/water, ethyl acetate.
(S)-1-Naphthylethylamine of 94% e.e., as produced in stage 4 was mixed with each of the above acids and the crystals which formed were collected and were analysed as described in stage 1 (a) and stage 4.
Acid Solvent Crystals e.e(%) (L)-malic acid ethanol /water Yes 94 methanol/water No isopropyl alcohol/waterYes 94 ethylacetate No (L)-Tartaric acid ethanol /water Yes 97 methanollwater Yes 94 isopropyl alcohol/waterYes 95 ethylacetate Yes 94 (L)-Chloropropionicethanol/water Yes >99 acid (LCPA) (L)-Mandelic acid ethanol /water Yes 95 methanol/water Yes ~ 94 isopropyl alcohol/waterYes 94 ethylacetate Yes 94 (L)-camphor acid ethanol /water Yes 94 methanol/water Yes 94 isopropyl alcohol/waterYes 94 ethylacetate No (L)-camphorsulfonicethanol /water Yes 94 acid methanol/water No isopropyl alcohoUwaterNo ethylacetate No A significant improvement in e.e. was only observed with (L)-tartaric acid (97%) and with LCPA (>99%) in ethanol/water.
Sta a 5 b Formation of the salt ci CH3 ~~NHz CH~COOH CH3 ,,.NHZHOOC~CH
/ / EtOH/H~0:10/90 ~ / /
A mixture of ethanol (1.68 ml) and water (15.1 ml) was added with stirring to the product of stage 4. (L)-Chloropropionic acid (6.38 g, 1 equivalent of the product of step 4) was then added dropwise to the stirred mixture. The mixture was then heated to 60°C
and stirred for a further 30 minutes. The reaction mixture was cooled to room temperature and then concentrated to 50% by volume in a rotary evaporator and then allowed to settle until the precipitated salt is fully formed.
Ste 5 c Formation of the Free Amine c1 CH ~
,~, NHa HOOC~CH3 CH ~~ NHZ
NaOH
\ \ ~ ~ \ \
/ / toluene / /
The salt from stage 5 (b) (4.53g) was dissolved in 25 ml of 5M NaOH. Toluene (25m1) was added to this solution while maintaining the pH above 10 by the addition of additional NaOH. The mixture was allowed to settle and the toluene solution was concentrated to dryness to yield the title product, as a yellow liquid, in greater than 99%
e.e.
Claims (22)
1. A process for the preparation of a compound of Formula (1):
wherein:
R x is optionally substituted aryl; and R y is optionally substituted hydrocarbyl:
which comprises the steps:
(a) reducing a compound of Formula (2):
to a compound of Formula (3):
wherein R x and R y are as defined for Formula (1):
(b) reacting a compound of Formula (3) with a leaving group donor, to give a compound of Formula (4);
wherein:
R x and R y are as defined for Formula (1); and OL is a leaving group:
(c) reacting a compound of Formula (4) with ammonia to give a compound of Formula (1).
wherein:
R x is optionally substituted aryl; and R y is optionally substituted hydrocarbyl:
which comprises the steps:
(a) reducing a compound of Formula (2):
to a compound of Formula (3):
wherein R x and R y are as defined for Formula (1):
(b) reacting a compound of Formula (3) with a leaving group donor, to give a compound of Formula (4);
wherein:
R x and R y are as defined for Formula (1); and OL is a leaving group:
(c) reacting a compound of Formula (4) with ammonia to give a compound of Formula (1).
2. A process according to claim 1 for the preparation of a compound of Formula (5):
wherein:
R1 is a substituent;
R2 is optionally substituted hydrocarbyl; and n is 0 to 4:
which comprises the steps:
(a) reducing a compound of Formula (6):
to a compound of Formula (7):
wherein R1, R2 and n are as defined for Formula (5):
(b) reacting a compound of Formula (7) with a leaving group donor, to give a compound of Formula (8);
wherein:
R1, R2 and n are as defined for Formula (5);
OL is a leaving group:
(c) reacting a compound of Formula (8) with ammonia to give a compound of Formula (5).
wherein:
R1 is a substituent;
R2 is optionally substituted hydrocarbyl; and n is 0 to 4:
which comprises the steps:
(a) reducing a compound of Formula (6):
to a compound of Formula (7):
wherein R1, R2 and n are as defined for Formula (5):
(b) reacting a compound of Formula (7) with a leaving group donor, to give a compound of Formula (8);
wherein:
R1, R2 and n are as defined for Formula (5);
OL is a leaving group:
(c) reacting a compound of Formula (8) with ammonia to give a compound of Formula (5).
3. A process according to claim 2 where R2 is optionally substituted C1-4alkyl.
4. A process according to claim 3 where R2 is methyl.
5. A process according to any one of the preceding claims wherein n is 0.
6. A process according to any one of the preceding claims where step (a) is carried out in the presence of a catalyst.
7. A process according to claim 6 where the catalyst is of Formula (A):
wherein:
R3 represents a neutral optionally substituted hydrocarbyl, a neutral optionally substituted perhalogenated hydrocarbyl, or an optionally substituted cyclopentadienyl ligand;
A represents -NR4-, -NR5-, -NHR4, -NR4R5 or -NR5R6 where R4 is H, C(O)R6, SO2R6, C(O)NR6R10, C(S)NR6R10, C(=NR10)SR11 or C(=NR10)OR11, R5 and R6 each independently represents an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, and R10 and R11 are each independently hydrogen or a group as defined for R6;
B represents -O-, -OH, OR7, -S-, -SH, SR7, -NR7-, -NR8-, -NHR8, -NR7R8, -NR7R9, -PR7- or -PR7R9 where R8 is H, C(O)R9, SO2R9, C(O)NR9R12, C(S)NR9R12, C(=NR12)R13 or C(=NR12)OR13, R7and R9 each independently represents an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, and R12 and R13 are each independently hydrogen or a group as defined for R9;
E represents a linking group;
M represents a metal capable of catalysing transfer hydrogenation; and Y represents an anionic group, a basic ligand or a vacant site;
provided that when Y is not a vacant site that at least one of A or B carries a hydrogen atom.
wherein:
R3 represents a neutral optionally substituted hydrocarbyl, a neutral optionally substituted perhalogenated hydrocarbyl, or an optionally substituted cyclopentadienyl ligand;
A represents -NR4-, -NR5-, -NHR4, -NR4R5 or -NR5R6 where R4 is H, C(O)R6, SO2R6, C(O)NR6R10, C(S)NR6R10, C(=NR10)SR11 or C(=NR10)OR11, R5 and R6 each independently represents an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, and R10 and R11 are each independently hydrogen or a group as defined for R6;
B represents -O-, -OH, OR7, -S-, -SH, SR7, -NR7-, -NR8-, -NHR8, -NR7R8, -NR7R9, -PR7- or -PR7R9 where R8 is H, C(O)R9, SO2R9, C(O)NR9R12, C(S)NR9R12, C(=NR12)R13 or C(=NR12)OR13, R7and R9 each independently represents an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, and R12 and R13 are each independently hydrogen or a group as defined for R9;
E represents a linking group;
M represents a metal capable of catalysing transfer hydrogenation; and Y represents an anionic group, a basic ligand or a vacant site;
provided that when Y is not a vacant site that at least one of A or B carries a hydrogen atom.
8. A process according to claim 7 wherein A-E-B, R3 and Y are chosen so that the catalyst is chiral.
9. A process according to either claim 7 or claim 8 wherein M, the metal, is rhodium present in valence state III and R3 is an optionally substituted cyclopentadienyl ligand.
10. A process according to any one of claims 7 to 9 where the catalyst of Formula (A) is of formula:
11. A process according to any one of the preceding claims wherein step (a) is a stereospecific reaction.
12. A process according to any one of the preceding claims wherein the product of step (a) is a compound of Formula (9):
wherein:
R1 is a substituent;
R2 is optionally substituted hydrocarbyl; and n is O to 4.
wherein:
R1 is a substituent;
R2 is optionally substituted hydrocarbyl; and n is O to 4.
13. A process according to any one of claims 1 to 5 where in step (b) the leaving group donor is a compound of formula R14SO2X, where R14 is an optionally substituted alkyl, optionally substituted aryl or an optionally substituted heteroaryl group and X is a halogen.
14. A process according to claim 13 where in step (b) the leaving group donor is methanesulphonyl chloride.
15. A process according to either claim 1 or claim 2 for the preparation of a compound of Formula (10):
which comprises the steps:
(a) reducing a compound of Formula (11):
to a compound of Formula (12):
(b) reacting a compound of Formula (12) with a compound of formula R3SO2X, in the presence of a base, to give a compound of Formula (13);
wherein:
R3 is optionally substituted C1-4alkyl; and X is halogen:
(c) reacting a compound of Formula (13) with ammonia to give a compound of Formula (10).
which comprises the steps:
(a) reducing a compound of Formula (11):
to a compound of Formula (12):
(b) reacting a compound of Formula (12) with a compound of formula R3SO2X, in the presence of a base, to give a compound of Formula (13);
wherein:
R3 is optionally substituted C1-4alkyl; and X is halogen:
(c) reacting a compound of Formula (13) with ammonia to give a compound of Formula (10).
16. A process according to claim 15 where step (a) is carried out in the presence of a catalyst of Formula (A) as described in claim 7.
17. A process according to claim 15 wherein the compound of Formula (10) is purified by diastereomeric salt resolution using (L)-tartaric acid or (L)-chloroproplonic acid.
18. A process for the preparation of a stereoisomer of a compound of Formula (14):
wherein:
R1 is a substituent;
R2 is optionally substituted hydrocarbyl; and n is O to 4:
which comprises the transfer hydrogenation of a compound of Formula (6):
by a hydrogen donor in the presence of a catalyst of Formula (A) as described in claim 7.
wherein:
R1 is a substituent;
R2 is optionally substituted hydrocarbyl; and n is O to 4:
which comprises the transfer hydrogenation of a compound of Formula (6):
by a hydrogen donor in the presence of a catalyst of Formula (A) as described in claim 7.
19. A process for the diastereomeric salt resolution of (S)-1-naphthylethylamine which comprises mixing (S)-1-naphthylethylamine with (2R,3R)-tartaric acid or (S)-chloropropionic acid to form the corresponding diastereomeric salt.
20. A diastereomeric salt of (S)-1-naphthylethylamine with (2R,3R)-tartaric acid or (S)-chloropropionic acid.
21. A compound of Formula (15):
wherein:
R1 is a substituent;
R2 is optionally substituted hydrocarbyl; and n is O to 4.
wherein:
R1 is a substituent;
R2 is optionally substituted hydrocarbyl; and n is O to 4.
22. A compound according to claim 21 of Formula (15) which is of Formula (16):
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GB0313661.1 | 2003-06-13 | ||
GBGB0313661.1A GB0313661D0 (en) | 2003-06-13 | 2003-06-13 | Process |
PCT/GB2004/002478 WO2004110976A2 (en) | 2003-06-13 | 2004-06-09 | Process for the preparation of aromatic amines |
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US (1) | US20060252964A1 (en) |
EP (1) | EP1636165A2 (en) |
JP (1) | JP2006527255A (en) |
CN (1) | CN1835909A (en) |
CA (1) | CA2529152A1 (en) |
GB (1) | GB0313661D0 (en) |
WO (1) | WO2004110976A2 (en) |
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GB0428128D0 (en) * | 2004-12-22 | 2005-01-26 | Avecia Ltd | Process |
CN101146801A (en) * | 2005-03-22 | 2008-03-19 | 霍夫曼-拉罗奇有限公司 | New salt and polymorphs of a dpp-iv inhibitor |
WO2008058235A2 (en) * | 2006-11-08 | 2008-05-15 | Dr. Reddy's Laboratories, Ltd. | Processes for the preparation of cinacalcet |
CN101407465B (en) * | 2007-10-12 | 2013-06-05 | 天津药明康德新药开发有限公司 | Method for preparing optical pure 1-(1-naphthyl)ethylamine by separation |
JP5727127B2 (en) | 2009-04-10 | 2015-06-03 | 関東化学株式会社 | Asymmetric catalyst and method for producing optically active alcohols using the same |
CN102617500B (en) * | 2011-01-31 | 2016-07-13 | 山东信立泰药业有限公司 | A kind of preparation method of linezolid intermediate, its preparation method and Linezolid |
WO2014178068A2 (en) * | 2013-04-08 | 2014-11-06 | Cadila Healthcare Limited | An improved process for preparation of n-[1-(1-naphthyl)ethyl] -3- [3-(trifluoromethyl)phenyl]propan-1-amine and pharmaceutically acceptable salts thereof |
CN103420845B (en) * | 2013-08-21 | 2015-09-02 | 中国药科大学 | One prepares the method for cinacalcet intermediate R-(+)-1-(1-naphthyl) ethamine |
CN105294449B (en) * | 2014-06-16 | 2017-02-08 | 连云港手性化学有限公司 | Preparation method for (R)-(+)-1-(1-naphthyl)ethylamine and (S)-(-)-1-(1-naphthyl)ethylamine |
CN104151171B (en) * | 2014-08-14 | 2016-07-27 | 六安佳诺生化科技有限公司 | The method of optical voidness R-1-naphthalene ethylamine is prepared in a kind of fractionation |
WO2017033134A1 (en) | 2015-08-26 | 2017-03-02 | Lupin Limited | Enzymatic process for the for preparation of (r)-1-(1-naphthyl) ethylamine, an intermediate of cinacalcet hydrochloride |
CN105085235A (en) * | 2015-08-31 | 2015-11-25 | 彭静 | Method for splitting and preparing S-4-chloro mandelic acid |
CN105085234A (en) * | 2015-08-31 | 2015-11-25 | 彭静 | Preparing method of (R)-(-)-4-chloromandelic acid |
CN105085244A (en) * | 2015-08-31 | 2015-11-25 | 彭静 | Preparing method of (R)-(+)-4-bromomandelic acid |
CN105085245A (en) * | 2015-08-31 | 2015-11-25 | 彭静 | Preparing method of (R)-(+)-4-fluoromandelic acid |
CN105061190A (en) * | 2015-09-02 | 2015-11-18 | 彭静 | Method for preparing S-five-fluorine amygdalic acid through resolution |
CN105085247A (en) * | 2015-09-02 | 2015-11-25 | 彭静 | Resolution preparation method of R-4-methoxymandelic acid |
CN105085236A (en) * | 2015-09-02 | 2015-11-25 | 彭静 | Resolution preparation method of R-pentafluoro DL-mandelic acid |
TWI784593B (en) | 2021-06-22 | 2022-11-21 | 陳慶祥 | tattoo machine |
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DE3431591A1 (en) * | 1984-08-28 | 1986-03-13 | Diamalt AG, 8000 München | METHOD FOR PRODUCING AMINO COMPOUNDS FROM HYDROXYL COMPOUNDS |
AU7446196A (en) * | 1995-10-13 | 1997-04-30 | Penn State Research Foundation, The | Asymmetric synthesis catalyzed by transition metal complexes with new chiral ligands |
GB9706321D0 (en) * | 1997-03-26 | 1997-05-14 | Zeneca Ltd | Catalytic hydrogenation |
YU29300A (en) * | 1997-11-12 | 2003-08-29 | The Penn State Research Foundation | Transition metal-catalyzed reactions based on chiral amine oxazolinyl lygands |
US6391865B1 (en) * | 1999-05-04 | 2002-05-21 | Schering Corporation | Piperazine derivatives useful as CCR5 antagonists |
CZ20013940A3 (en) * | 1999-05-04 | 2002-04-17 | Schering Corporation | Piperazine derivatives useful as CCR5 antagonists |
JP3938651B2 (en) * | 2000-04-13 | 2007-06-27 | セントラル硝子株式会社 | Process for producing optically active α-methyl-bis-3,5- (trifluoromethyl) benzylamine |
-
2003
- 2003-06-13 GB GBGB0313661.1A patent/GB0313661D0/en not_active Ceased
-
2004
- 2004-06-09 EP EP04736423A patent/EP1636165A2/en not_active Withdrawn
- 2004-06-09 CA CA002529152A patent/CA2529152A1/en not_active Abandoned
- 2004-06-09 CN CNA2004800231778A patent/CN1835909A/en active Pending
- 2004-06-09 WO PCT/GB2004/002478 patent/WO2004110976A2/en active Application Filing
- 2004-06-09 US US10/560,305 patent/US20060252964A1/en not_active Abandoned
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JP2006527255A (en) | 2006-11-30 |
US20060252964A1 (en) | 2006-11-09 |
GB0313661D0 (en) | 2003-07-16 |
CN1835909A (en) | 2006-09-20 |
EP1636165A2 (en) | 2006-03-22 |
WO2004110976A3 (en) | 2005-04-21 |
WO2004110976A2 (en) | 2004-12-23 |
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